2,6-Methano-3-benzazocines

ABSTRACT

6(EQ)-R 4  -1,2,3,4,5,6-Hexahydro-3-R 1  -11(ax)-R 3  -11(eq)-CH 2  Z-2,6-methano-3-benzazocines, useful as analgesic agents and narcotic antagonists, and 1-R 1  -2-Q-4aα-R 3  -5α-R 4  -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethano- (and 3,5-ethano) benzo[g]quinolines, useful as analgesic agents, prepared by heating, with formic acid in an organic solvent or with certain ammonium formates in the absence of a solvent, certain 1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines, the latter prepared by acid catalyzed cyclization of a 3-benzyl-2-azabicyclo[2.2.2]-oct-5-ene.

RELATED APPLICATIONS

This is a continuation-in-part of my prior, copending applications Ser. No. 695,977, filed June 14, 1976, and Ser. No. 576,313, filed May 12, 1975, both now abandoned, application Ser. No. 695,977 being in turn also a continuation-in-part of application Ser. No. 576,313, which in turn is a continuation-in-part of my prior application Ser. No. 471,571, filed May 20, 1974, now U.S. Pat. No. 3,932,422, patented Jan. 13, 1976.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 11(eq)-substituted-2,6-methano-3-benzazocines useful as analgesics and narcotic antagonists.

2. Description of the Prior Art

2,6-Methano-3-benzazocines substituted in the 11-position with a lower-alkyl group are known. (See for example Gordon et al. U.S. Pat. No. 2,924,603, patented Feb. 9, 1960). Moreover, it is known that compounds in the 6,14-endo-etheno- and ethanotetrahydrothebaine and 6,14-endo-etheno- and ethanotetrahydrooripavine series having ketone, carbinol or lower-alkenyl groups at the 7-position thereof have unusual analgesic potency relative to morphine. [See Bentley et al., J. Am. Chem. Soc. 89, 3267-3292 (1967)]. Consequently there has been much interest in the field of analgesics in incorporating the ketone, carbinol or lower-alkenyl function present in the latter series at the 11-position of 2,6-methano-3-benzazocine-type analgesics, but all synthetic efforts in this direction have previously been unsuccessful.

SUMMARY OF THE INVENTION

In one of its composition of matter aspects, the invention relates to certain 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ '''-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines, where Z is a ketone, carbinol or lower-alkenyl function and R₁, R₂, R₂ ', R₂ ", R₂ ''', R₃ and R₄ are hydrogen, lower-alkyl or other organic groups more specifically defined hereinafter, which are useful as analgesics and narcotic antagonists.

In another composition of matter aspect, the invention relates to certain 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-etheno- (and 3,5-ethano-)-benzo[g]quinolines useful as analgesics and narcotic antagonists.

In another composition of matter aspect, the invention relates to certain 2-R₁ -3-(4-R₂ -3-R₂ "-5-R₂ '-6-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-enes, where Y' is carboxy, cyano, carbo-lower-alkoxy or lower-alkanoyl, which are useful as intermediates for the preparation of the above-described octahydro-2,5-methanobenzo[g]quinolines and hexahydro-2,6-methano-3-benzazocines.

In another composition of matter aspect, the invention relates to certain 6R₂ "-7-R₂ -8-R₂ '-9-R₂ "'-1-R₁ -3-Y-3-R₈ -4aα-R₃ -5α-R₄ -1, 2,3,4,4a,5,10,10a, octahydro-2,5-methanobenzo[g]quinolines, where Y is certain oxygenated functions more specifically defined hereinafter, which are useful as intermediates for the preparation of the above-described hexahydro-2,6-methano-3-benzazocines, certain species being also useful as analgesic agents.

In one of its process aspects, the invention relates to a process for preparing certain 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ '''-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines comprising heating with formic acid in an inert organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate certain 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines.

In another of its process aspects, the invention relates to a process for preparing certain 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines comprising heating with formic acid in an inert organic solvent or with a benzyl-di-lower-alkylammonium formate or a tri-lower-alkylammonium formate certain 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines.

DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS

More specifically this invention has, as its ultimate object, the obtainment of a new class of chemical compounds, useful as analgesics and narcotic antagonists, having the formula I: ##STR1## and chemically designated 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ '''-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines.

The new 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ "-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I and other novel intermediates useful in their preparation are obtained according to my invention by novel reactions, including molecular rearrangements involving novel intermediates, according to the general reaction sequence as follows: ##STR2##

Thus the 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ '''-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines having the formula I are prepared via any of several methods from the intermediate 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -3-Y-3-R₈ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines of formula II, which themselves are obtained from the 2-R₁ -3-(4-R₂ -3-R₂ " [or 5-R₂ ]-6-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-enes of formula IV which, in turn, are prepared according to standard procedures by reaction of a Grignard reagent derived from a 4-R₂ -3-R₂ '- (or R₂ ")-2-R₂ '''-benzyl halide of formula VI with a 3-R₃ -4-R₄ -1-R₁ -pyridinium halide of formula VII and reaction of the resulting 1-R₁ -2-(4-R₂ -3-R₂ ' [or R₂ "]-2-R₂ '''-benzyl)-3-R₃ -4-R₄ -1,2-dihydropyridine of formula VIII with a dienophile, CH₂ ═CHY'. The 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formula IIIa are obtained along with certain compounds of formula I from the compounds of formula II where Y is COR₅ and R₈ is hydrogen, and the compounds of formula IIIa are also obtainable by rearrangement of a 3-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-4-R₃ -5-R₄ -2-azabicyclo[2.2.2]-oct-5-ene-7-carboxylic acid ester of formula IV to a 1-R₃ -2-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-8-lower-alkylidene-3-azabicyclo[3.3.1]non-6-en-4-one of formula V and cyclization of the latter to a 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-2-oxo-4 aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline having the formula IIIa. The compounds of formula IIIa can be catalytically reduced to the 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinolines of formula IIIb.

In the final products and intermediates depicted in the above reaction sequences:

R₁ is hydrogen, lower-alkyl, lower-alkanoyl only when R₄ is hydrogen, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl, or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups, phenyl-lower-alkyl, or phenyl-lower-alkyl substituted in the phenyl ring by from one to two members of the group consisting of halogen (including bromine, chlorine and fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, amino, lower-alkanoylamino or a single methylenedioxy attached to adjacent carbon atoms;

R₂, r₂ ' r₂ " and R₂ ''' are each hydrogen, or three of them are hydrogen and the fourth is halogen (including bromine, chlorine or fluorine), lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methylenedioxy;

R₃ is hydrogen or lower-alkyl;

R₄ is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkyl-sulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R₃ and R₄ together are divalent lower-alkylene, --(CH₂)_(n) --, where n is one of the integers 3 or 4;

R₄ ' is hydrogen or lower-alkyl;

Z is one of the groups ##STR3## or the ethylene glycol ketal thereof, ##STR4## or a group of the formula: ##STR5## where

R₅ and R₆ are the same or different hydrogen, lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl;

R₇ is hydrogen, lower-alkanoyl, benzoyl, or benzoyl substituted by from one to three members of the group consisting of lower-alkyl, lower-alkoxy, hydroxy, halo (including chlorine, bromine and fluorine) or trifluoromethyl;

R₈ is hydrogen or lower-alkyl;

R₉ is lower-alkyl, cycloalkyl-lower-alkyl or phenyl-lower-alkyl;

Q is oxo ##STR6##

Y is carboxy, cyano, carbo-lower-alkoxy, COR₅, COO-- lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl, or a group of the formula: ##STR7##

Y' is carboxy, cyano, carbo-lower-alkoxy, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl or lower-alkanoyl; and Hal is halogen.

As used herein, the terms lower-alkyl or lower-alkoxy mean saturated, acyclic groups which may be straight or branched containing from one to about seven carbon atoms as exemplified by methyl, ethyl, propyl, isopropyl, butyl, nonadjacent t-butyl, methoxy, ethoxy, propoxy, isopropoxy, or t-butoxy.

As used herein, the terms lower-alkenyl, halo-lower-alkenyl and lower-alkynyl represent monovalent groups of from three to seven carbon atoms containing one double or triple bond as illustrated, for example by 1-propenyl, 2-butenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-propynyl, 2-butynyl, 4-pentynyl, 2-hexynyl, and the like. The term halo-lower-alkenyl includes, for example, 2-chloroethenyl, 2-bromoethenyl, 3,3-dichloro-2-propenyl, 1-bromo-2-methylpropenyl, and the like.

As used herein, the term cycloalkyl means saturated carbocyclic groups containing from three to seven ring carbon atoms as illustrated, for example, by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclobutyl, 4-ethylcyclohexyl, and the like.

As used herein, the term lower-alkanoyl means such groups derived from saturated, aliphatic monocarboxylic acids having from one to four carbon atoms, as illustrated, for example, by formyl, acetyl, propionyl, butyryl, isobutyryl, and the like.

As used herein, the term lower-alkylene means a saturated, divalent radical, which can be straight or branched, and having from one to four carbon atoms, as illustrated, for example, by methylene [--CH₂ --], 1,2-ethylene [--CH₂ CH₂ --], 1,3-propylene [--CH₂ CH₂ CH₂ --], 1,2-(1-methylethylene) [--CH(CH₃)CH₂ --], 1,4-butylene [--CH₂ CH₂ CH₂ CH₂ --], and the like.

As determined by standard pharmacological test procedures to be described hereinafter, the compounds of formula I and certain species of formula II have been found to have useful analgesic activity, and as disclosed following Example 38B infra, some compounds of formula I have also been found to have useful narcotic antagonist activity. The compounds of formula I are thus useful as analgesic agents and narcotic antagonists, and certain species of formula II are useful as analgesic agents. The compounds of formula III have also been found to have analgesic activity and are thus useful as analgesic agents.

Preferred compounds within the ambit of formula I are those where Z is the group CH₂ COR₅ where R₅ is lower-alkyl and R₁, R₂, R₂ ', R₂ ", R₂ ''', R₃ and R₄ have the meanings given above, and particularly preferred compounds are those of the latter type where R₁, R₃ and R₄ are each lower-alkyl; R₂ is hydroxy; and R₂ ', R₂ " and R₂ ''' are each hydrogen.

In accordance with the above general description, the 7-R₂ "-8-R₂ -9-R₂ '-10-R₂ '''-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I where Z is ##STR8## and R₁, R₂, R₂ ', R₂ ", R₂ ''', R₃, R₄, R₅, R₆ and R₈ have the meanings given above are prepared by heating, with formic acid in an organic solvent, for example toluene, xylene or mesitylene, or with a benzyl-di-lower-alkylammonium or a tri-lower-alkylammonium formate, a 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -3-Y-3-R₈ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formula II where R₈ is hydrogen and Y is either COR₅ (to give the compounds of formula I where Z is CH₂ COR₅) or the group: ##STR9## where R₇ is hydrogen (to give the compounds of formula I where ##STR10## A preferred solvent is mesitylene. The compounds of formula II where Y is COR₅ or the group ##STR11## where R₇ is hydrogen are thus intermediates for preparing the compounds of formula I where Z is, respectively, the groups ##STR12##

The compounds of formula I where Z is ##STR13## where R₈ is lower-alkyl, are prepared by treatment of the compounds of formula IIB, where R₈ is hydrogen and Y is a proton activating group, i.e. an ester or keto (COR₅) group, with a strong base, for example a lithium di-lower-alkylamide, a preferred base being lithium diisopropylamide, and reaction of the resulting lithium salt with a lower-alkyl ester of a strong mineral acid, for example a lower-alkyl halide or a di-lower-alkyl sulfate. The ester or keto group Y in the compounds of formula IIA thus obtained can then be converted to other groups, for example ##STR14## before conversion of the latter to the compounds of formula I where Z is ##STR15## and R₈ is lower-alkyl by heating the compounds of formula II where R₈ is lower-alkyl with formic acid in an organic solvent or with a benzyl-di-lower-alkylammonium or tri-lower-alkylammonium formate as described above.

As indicated in the above reaction sequence, alkylation of the compounds of formula IIB via the lithium salt results in epimerization of the Y group. It had been previously thought that the group Y in the compounds of formula IIB as obtained by cyclization of the compounds of formula IV possesses the β-configuration, i.e. the group Y is cis to the 2,5-methano bridge (vide infra), and such steric configuration of the group Y is disclosed in Sterling Drug Inc.-owned Japanese Provisional Patent Publication No. 160,275, published Dec. 26, 1976 from Japanese Pat. Appln. No. 60,111/75, filed May 20, 1975 as well as in U.S. Pat. No. 3,932,422, patented Jan. 13, 1976 on application Ser. No. 471,571, filed May 20, 1974 and on which Japanese Appln. No. 60,111/75 was based. However, since the time of preparation and filing of the Japanese application in which the patent publication is based, some uncertainty has developed over whether the group Y has the α- or β-configuration. In any event, alkylation of the compounds of formula IIB via the lithium salt results in epimerization of the group Y, and in fact, the compounds of formula IIA where R₈ is hydrogen and the Y group is in either the α- or the β-configuration can be prepared from the respective β-Y or α-Y compounds by treatment first with a strong base and then with acid. In view of the fact then that either of the groups Y and R₈ in the compounds of formulas IIA and IIB, respectively, can occupy either the α- or the β-configuration, the compounds of formulas IIA and IIB can be generally represented by the formula: ##STR16## where R₈ is hydrogen or lower-alkyl.

Insofar as the structures of the 2,6-methano-3-benzazocines of formula I are concerned, the question of the steric configuration at the 3-position of the compounds of formula II is moot, because the asymmetry at the 3-position is destroyed on conversion of the compounds of formula II to the compounds of formula I, and the compounds of formula II having both possible steric configurations at the 3-position are fully operable for the preparation of the compounds of formula I.

Insofar as the steric configuration of the group Q in the compounds of formula IIIa is concerned, a study of molecular models of hypothetical reaction intermediates indicates that the group Q probably has the β-configuration, i.e. Q is cis to the 3,5-etheno bridge, but the configuration has not been rigorously established.

The compounds of formula I where Z is the group: ##STR17## where R₇ is hydrogen and R₅, R₆ and R₈ have the meanings given above are prepared from the corresponding compounds where Z is the group ##STR18## by hydroxylation of the latter, for example with concentrated sulfuric acid and hydrolysis of the resulting hydrogen sulfate ester. The compounds of formula I where Z is the group ##STR19## are thus intermediates for the carbinols of formula I.

The compounds of formula I where Z is the group ##STR20## where each of R₆ and R₇ is hydrogen and R₅ and R₈ have the meanings given above are prepared by selective reduction of the corresponding compounds where Z is ##STR21## When R₅ is hydrogen the selective reduction is carried out with an alkali metal aluminum hydride in an inert organic solvent such as dioxane, tetrahydrofuran or diethyl ether at temperatures in the range from about 0° C. to 100° C. When R₅ is lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl, the reduction is carried out with an alkali metal borohydride in an inert organic solvent, for example lower-alkanols, such as methanol, ethanol or isopropanol.

The compounds of formula I where Z is ##STR22## R₅ and R₆ are each lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl, R₇ is hydrogen and R₈ is hydrogen or lower-alkyl are prepared by reaction of the corresponding compounds where Z is ##STR23## where R₅ is lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl with one molar equivalent of an appropriate organo lithium, R₆ Li, where R₆ has the meanings given above. The reaction is carried out in an inert organic solvent such as benzene or toluene. In this manner compounds where R₅ and R₆ are either the same or different lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl groups can be prepared depending upon the identity of the R₅ group and the choice of the particular organo lithium.

The compounds of formula I where Z is ##STR24## R₅ and R₆ are each hydrogen or the same or different lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl, R₈ has the meanings given above, and R₇ is lower-alkanoyl, benzoyl or substituted-benzoyl are prepared by esterification of the corresponding compounds where R₇ is hydrogen, for example with an appropriate acid halide, anhydride or other acylating agent. The reaction is advantageously carried out using an appropriate acid halide in a pyridine solvent which serves as an acid acceptor to take up the hydrogen halide split out during the course of the reaction.

The compounds of formula I where R₁ is lower-alkenyl, lower-alkynyl, halo-lower-alkenyl or 2- or 3-furylmethyl (or such 2- or 3-furylmethyl substituted by from one to three methyl groups) are advantageously prepared from the corresponding compounds where R₁ is hydrogen by reaction of the latter with an appropriate lower-alkenyl halide, lower-alkynyl halide or halo-lower-alkenyl halide, as the case may be, in an inert organic solvent, for example a lower-alkanol, acetone or dimethylformamide (hereinafter designated DMF), in the presence of an acid-acceptor, for example an alkali metal carbonate or bicarbonate. A preferred solvent is DMF.

The compounds of formula I where R₂, R₂ ', R₂ " or R₂ ''' is lower-alkanoyloxy are advantageously prepared from the corresponding compounds where R₂, R₂ ', R₂ " or R₂ ''' is hydroxy by esterification with an appropriate lower-alkanoyl halide in the presence of pyridine.

The compounds of formula I where R₂, R₂ ', R₂ " or R₂ ''' is amino are prepared by hydrolysis of the corresponding compounds where R₂, R₂ ', R₂ " or R₂ ''' is lower-alkanoylamino or lower-alkoxycarbonylamino by heating the latter in aqueous alkali.

Alternatively, the compounds of formula I where R₂, R₂ ', R₂ " or R₂ ''' is amino are prepared by reaction of the compounds of formula I where Z is ##STR25## and R₁ is hydrogen with nitric acid in glacial acetic acid. The reaction is carried out at temperatures from 0° to 5° C. The resulting nitro compound is then alkylated as desired in the manner described above to prepare compounds where R₁ has the other various meanings given above, and in a final step, the nitro groups is reduced to the corresponding amino group by either catalytic means, for example with hydrogen over palladium-on-charcoal, or by chemical means, for example by iron and hydrochloric acid or by tin and hydrochloric acid.

As indicated in the reaction sequence shown above, the 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formula IIIa where Q is H₂, CH-lower-alkyl, CH-cycloalkyl-lower-alkyl, CH-phenyl or CH-lower-alkyl-phenyl are produced along with the compounds of formula I (where Z is --CH₂ COR₅) when the compounds of formula II where Y is COR₅ and R₈ is hydrogen are heated with formic acid in an organic solvent or with a benzyl-di-lower-alkyl ammonium formate or a tri-lower-alkylammonium formate as described above. When the benzazocines of formula I are the desired product, it is preferred to carry out the reaction in mesitylene using a concentration of 0.05 molar in starting material of formula II and 1.0 molar in formic acid. This mixture gives a reaction temperature at reflux of about 120° C. and affords the benzazocines of formula I and the benzo[g]-quinolines of formula IIIa in a ratio of from 2:1 to 3:1. By progressively decreasing the formic acid concentration, successively higher boiling mixtures are produced, which result in production of progressively increased relative amounts of the benzo[g]quinolines. Thus at formic acid concentrations of 0.5 molar and 0.15 molar (and 0.05 molar in starting material), the benzo[g]quinolines and benzazocines are produced in ratios of about 2:1 and 7:1, respectively. Similarly, by using a ratio of 1 mole of starting material to 5 moles of, respectively, benzyldimethylammonium formate or trimethylammonium formate or triethylammonium formate and heating the mixture (in the absence of any organic solvent) at 150° C. for about 15 minutes, a mixture of benzo[g]quinoline and benzazocine is produced in ratios of 10:1, 3:1 and 20:1, respectively.

The two transformations thus take place simultaneously under the given conditions and are best seen by reference to the reaction sequence: ##STR26## where R₁, R₂, R₂ ', R₂ ", R₂ ''', R₃, R₄, R₅, R₈ and Q have the meanings given above. It will be seen from the above that the compounds of formula I result by rupture, under the reaction conditions, of bond (b) in the compounds of formula II, whereas the compounds of formula IIIa result when bond (a) is broken, followed by ring closure between the nitrogen atom and the carbonyl group of the COR₅ moiety.

The compounds of formula IIIa where Q is oxo (=O), R₁ is hydrogen and R₄ is lower-alkyl are prepared by reaction of a 3-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-ene of formula IV where R₁ is hydrogen and Y' is COOR₉ with an alkali metal lower-alkoxide in a lower-alkanol solvent at a temperature in the range from 20° to 80° C. followed by heating the resulting 1-R₃ -2-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-8-lower-alkylidene-3-azabicyclo[3.3.1]non-6-en-4-one of formula V with a mineral acid. The method is represented by the reaction sequence: ##STR27##

As indicated, the rearrangement of the compounds of formula IV to the compounds of formula V takes place by cleavage of the bond designated (c) in formula IV, cyclization of the ester group, COOR₉, to the nitrogen atom with formation of the lactam, shift of the endocyclic double bond and generation of an exocyclic double bond with loss of a proton from the R₄ lower-alkyl group. It will also be seen from the above-depicted reaction sequence that cyclization of the compounds of formula V to the compounds of formula III can take place either at the 2- or 6-position of the benzyl group to give rise to compounds of formula IIIa where the R₂ ' (or R₂ ") group occupies either the 6- or 8-position of the latter.

Furthermore, it will also be appreciated that the cyclization affords the compounds where both the R₃ and R₄ groups are in the α-configuration, i.e. trans to the 3,5-etheno bridge (vide infra).

The compounds of formula IIIa where Q is H₂ and R₁ is hydrogen are prepared by reduction of the corresponding compounds where Q is oxo (=O) with an alkali metal aluminum hydride. The reaction takes place in an organic solvent inert under the conditions of the reaction, for example diethyl ether, dibutyl ether, tetrahydrofuran, dioxane and the like, at a temperature in the range from 20° C. to 100° C.

The compounds of formula IIIa where R₁ is other than hydrogen are advantageously prepared by reaction of the compounds where R₁ is hydrogen with an appropriate lower-alkyl, lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, 2- or 3-furylmethyl (or 2- or 3-furylmethyl substituted by from one to three methyl groups), phenyl-lower-alkyl or substituted-phenyl-lower-alkyl ester of a strong mineral acid, such as esters of hydrochloric, hydrobromic or sulfuric acid. The reaction is preferably carried out in the presence of an acid-acceptor, for example an alkali metal carbonate or bicarbonate, and in an inert organic solvent such as methanol, ethanol, acetone, isopropanol and the like.

The 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -2-Q-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinolines of formula IIIb are prepared by catalytic reduction of the corresponding 3,5-etheno compounds of formula IIIa with hydrogen over a palladium-on-charcoal catalyst using an inert organic solvent, for example methanol, ethanol or isopropanol.

The 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '''-1-R₁ -3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines of formula II which, as described above, serve as key intermediates for the preparation of the final products of formulas I, IIIa and IIIb are in turn prepared as follows:

The compounds of formula II where Y is carboxy, cyano, carbo-lower-alkoxy, COR₅, COO-lower-alkylene-cycloalkyl or COO-lower-alkylene-phenyl are prepared by the acid catalyzed cyclization of an appropriate 2-R₁ -3-(4-R₂ -3-R₂ '-[or 5-R₂ "]-2-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-ene of formula IV, where R₅ is lower-alkyl. The compounds of formula II where R₄ is hydrogen are prepared from the corresponding compounds of formula IV where R₁ is lower-alkanoyl. The reaction is carried out by adding the starting material of formula IV to the acid and either allowing the reaction mixture to stand at a temperature in the range from about 0° C. to about 10° C. or heating to about 100° C. Preferred acids are hydrofluoric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. A particularly preferred acid is hydrofluoric acid.

As in the case of the cyclization of the compounds of formula V to the compounds of formula IIIa, cyclization of the compounds of formula IV to the compounds of formula II can take place at either the 2- or the 6-position of the benzyl group to produce compounds of formula II where the R₂ ' (or R₂ ") group occupies either the 6- or the 8-position of the latter. And furthermore, as in the cyclization of the compounds of formula V to the compounds of formula IIIa, cyclization of the compounds of formula IV to those of formula II affords the compounds where both the R₃ and the R₄ groups are in the α-configuration, i.e. trans to the 2,5-methano bridge.

Moreover, during the course of the cyclization reaction, various ester or ether groups, [e.g. compounds where Y' in the compounds of formula IV or Y in the compounds of formula II is an ester group or one of R₂, R₂ ', R₂ " or R₂ ''' is, for example, lower-alkoxy] are often cleaved to the respective carboxylic acid or the phenolic compound, particularly when the reaction mixture is heated using, for example, hydrobromic acid. In such cases the products must be re-esterified or realkylated using standard procedures, if the esters or the ethers are the desired product. This circumstance is readily obviated if desired by use of hydrofluoric acid as the acid catalyst which only requires a reaction temperature of around 0°-10° C. Under these mild conditions, ester and ether groups remain unchanged during the reaction.

The above described method for the preparation of compounds of formula II is particularly advantageous for the preparation of compounds of formula II where Y is carboxy, cyano, carbo-lower-alkoxy, COR₅, COO-lower-alkylene-cycloalkyl or COO-lower-alkylene-phenyl where R₅ is lower-alkyl. The compounds of formula II where Y is the group ##STR28## where R₅, R₆ and R₇ have the meanings given above are advantageously prepared from the compounds of formula II where Y has the other meanings given above by methods involving various transformations of the Y group as carboxy, carboxylic acid ester or COR₅ as described above in connection with the preparation of the compounds of formula I.

The compounds of formula II where Y is carboxy, cyano, carbo-lower-alkoxy, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl, or a group of the formula: ##STR29## where one or both of R₅ and R₆ is hydrogen or lower-alkyl, and R₇ has the same meanings as in formula I can be converted to the compounds of formula II where Y is a COR₅ group by simple chemical transformations such as hydrolysis of a nitrile or ester to the carboxylic acid, or saponification of an ester of an hydroxymethyl-bearing compound (R₅, R₆ and R₇ are hydrogen) and oxidation of the hydroxymethyl group to the carboxylic acid. The latter can then be reacted with two moles of an appropriate organo lithium, R₅ Li, or the ester (Y is carbo-lower-alkoxy) can be reacted with one mole of an appropriate sterically hindered organo lithium, e.g. t-butyl lithium, to produce, in either case, the compounds where Y is COR₅. Compounds of formula II where R₇ and one of R₅ and R₆ is hydrogen and the other is lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl can likewise be converted to the compounds where Y is COR₅ by oxidation. The compounds of formula II where Y has the above-indicated meanings are thus also useful as intermediates for preparing the compounds of formula II where Y is COR₅, which in turn are useful as intermediates for the preparation of the compounds of formula I.

The compounds of formula II where Y is the group ##STR30## where R₅ and R₆ are hydrogen, lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl and R₇ is hydrogen, which as indicated above are intermediates for preparing the compounds of formula I, are prepared by saponification of the corresponding compounds where R₇ is lower-alkanoyl, benzoyl or substituted-benzoyl. The compounds of formula II where R₇ is lower-alkanoyl, benzoyl or substituted-benzoyl are thus intermediates for the compounds where R₇ is hydrogen. The ester forms are useful compounds for purification of the carbinols and serves as intermediates for the latter.

The compounds of formulas I or II where R₁ is benzyl can be catalytically debenzylated to give the corresponding compounds where R₁ is hydrogen. The latter can then be realkylated with an appropriate alkylating agent to give other different compounds where R₁ has the meanings given above. Reduction is carried out in an inert organic solvent, for example ethanol, isopropanol, and the like, and at pressures from 40 to 100 pounds p.s.i. A preferred catalyst is palladium-on-charcoal. The alkylation of the compounds of formula II where R₁ is hydrogen is carried out in an inert organic solvent, for example acetone, ethanol or DMF, and in the presence of an acid-acceptor, for example alkali metal carbonates or bicarbonates.

Finally the 2-R₁ -3-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-enes of formula IV, which serve as intermediates for the preparation of the key intermediates of formula II are themselves prepared by reaction of a Grignard reagent derived from a 4-R₂ -3-R₂ ' (or 5-R₂ ")-2-R₂ '''-benzyl halide of formula VI with an appropriate 3-R₃ -4-R₄ -1-R₁ -pyridinium halide of formula VII followed by Diels-Alder condensation of the resulting 1-R₁ -2-(4-R₂ -3-R₂ ' [or 5-R₂ "]-2-R₂ '''-benzyl)-3-R₃ -4-R₄ -1,2-dihydropyridine of formula VIII with an appropriate dienophile, CH₂ ═CHY'.

The reaction with the Grignard reagent is carried out at a temperature in the range from 0° C. to 25° C. in an inert organic solvent, for example diethyl ether, tetrahydrofuran or dibutyl ether and is effected by addition of a solution of the Grignard to a suspension of the quaternary salt in the reaction solvent. The resulting dihydro compound of formula VIII is generally not isolated and purified, but rather is carried forward directly to the next step involving reaction with the dienophile without further purification. The reaction of the dihydro compounds of formula VIII with the dienophile can either be carried out in an excess of the latter as a solvent or in an inert organic solvent such as benzene, toluene or xylene. Reaction is preferably carried out at the reflux temperature of the mixture.

The 3-R₃ -4-R₄ -pyridines, from which the quaternaries of formula VII are prepared, and also the 4-R₂ -3-R₂ '- (or 5-R₂ ")-2-R₂ '''-benzyl halides, from which the Grignard reagents are prepared, are known classes of compounds.

Due to the presence of a basic amino grouping, the free base forms represented by formulas I, II, IIIa, IIIb and IV above react with organic and inorganic acids to form acid-addition salts. The acid-addition salt forms are prepared from any organic or inorganic acid. They are obtained in conventional fashion, for instance either by direct mixing of the base with the acid or, when this is not appropriate, by dissolving either or both of the base and the acid separately in water or an organic solvent and mixing the two solutions, or by dissolving both the base and the acid together in a solvent. The resulting acid-addition salt is isolated by filtration, if it is insoluble in the reaction medium, or by evaporation of the reaction medium to leave the acid-addition salt as a residue. The acid moieties or anions in these salt forms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with the base.

Representative acids for the formation of the acid-addition salts include formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, trifluoroacetic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tannic acid, glutamic acid, tartaric acid, oxalic acid, pyromucic acid, citric acid, lactic acid, glycolic acid, gluconic acid, saccharic acid, ascorbic acid, penicillin, benzoic acid, phthalic acid, salicyclic acid, 3,5-dinitrobenzoic acid, anthranilic acid, cholic acid, 2-pyridinecarboxylic acid, pamoic acid, 3-hydroxy-2-naphthoic acid, picric acid, quinic acid, tropic acid, 3-indoleacetic acid, barbituric acid, sulfamic acid, methanesulfonic acid, ethanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, butylarsonic acid, methanephosphonic acid, acidic resins, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, arsenic acid, and the like.

All of the acid-addition salts are useful as sources of the free base forms, by reaction with an inorganic base. It will thus be appreciated that if one or more of the characteristics, such as solubility, molecular weight, physical appearance, toxicity, or the like of a given base or acid-addition salt thereof render that form unsuitable for the purpose at hand, it can be readily converted to another, more suitable form. For pharmaceutical purposes, acid-addition salts of relatively non-toxic, pharmaceutically-acceptable acids, for example hydrochloric acid, lactic acid, tartaric acid, and the like, are of course employed.

The compounds of this invention can exist in stereo-chemically isomeric forms, that is, optical isomers and geometric isomers. If desired, the isolation or the production of a particular stereochemical form can be accomplished by application of the general principles known in the prior art. In the nomenclature employed for the compounds of formula I herein, "ax" stands for axial and "eq" for equatorial, and the configurations are given with reference to the hydroaromatic ring. Thus, the 6(eq), 11(ax) compounds of formula I are in the cis configuration, whereas the 6(eq), 11(eq) compounds are in the trans configuration.

In the nomenclature employed for the compounds of formulas II, IIIa and IIIb, again configurations are given with reference to the hydroaromatic ring, and the designation "β" indicates the cis configuration relative to the 2,5-methano bridge of the compounds of formula II or the 3,5-ethano (or 3,5-etheno) bridge of the compounds of formulas IIIa and IIIb. Conversely, the designation "α" indicates the trans configuration relative to the same groups.

In standard pharmacological test procedures, the compounds of formulas I, IIIa and IIIb and the acid-addition salts thereof have been found useful as depressants of the central nervous system, and more particularly have been found useful as analgesics and as antagonists of strong analgesics such as phenazocine, meperidine and morphine. In addition, particular species of the compounds of formula II have been found useful as analgesics.

The compounds of formulas I, II, IIIa and IIIb can be administered in the same manner as known analgesics and antagonists of strong analgesics, i.e. parenterally or orally in any of the conventional pharmaceutical forms, as for instance solutions, suspensions, tablets, capsules, and the like.

As described above and as will be seen hereinbelow, many of the species of formulas I, II, IIIa, IIIb and IV are readily interconvertible by simple and well-known reactions such as reduction, oxidation, hydrolysis, esterification, etherification, and the like, so that they are also useful as intermediates for each other.

The useful properties of the compounds of this invention were demonstrated by standard pharmacological procedures readily carried out by technicians having ordinary skill in pharmacological test procedures, so that the actual determination of the numerical biological data definitive for a particular test compound can be ascertained without the need for any extensive experimentation.

The test procedures used to determine the analgesic and analgesic antagonist activities of the compounds of the invention have been described in detail in the prior art and are as follows: the acetylcholine-induced abdominal constriction test, which is a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholine-induced abdominal constriction in mice, described by Collier et al., Brit. J. Pharmacol. Chemotherap. 32, 295 (1968); a modification of the anti-bradykinin test, which is also a primary analgesic screening procedure, described by Berkowitz et al., J. Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J. Pharm. Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6, 312-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966); the phenyl-p-quinone-induced writhing test, also a primary analgesic screening test, designed to measure the ability of a test agent to prevent phenyl-p-quinone-induced writhing in mice, described by Pearl and Harris, J. Pharmacol. Exptl. Therap. 154, 319-323 (1966); the rat tail flick radiant thermal heat analgesic (agonist) test described by D'Amour and Smith, J. Pharmacol. Exptl. Therap. 72, 74 (1941) as modified by Bass and VanderBrook, J. Am. Pharm. Assoc. Sci. Ed. 41, 569 (1956); and the phenazocine antagonist test, which is designed to measure the ability of a test agent to antagonize the effect of phenazocine in the above-indicated rat tail flick response test, described by Harris and Pierson, J. Pharmacol. Exptl. Therap. 143, 141 (1964).

The structures of the compounds of this invention were established by the modes of synthesis, by elementary analyses and by ultraviolet, infrared and nuclear magnetic resonance spectra. The course of reactions and homogeneity of the products were ascertained by thin layer chromatography.

The manner and process of making and using the invention, and the best mode contemplated by the inventor of carrying out this invention, will now be described so as to enable any person skilled in the art to which it pertains to make and use the same. The melting points are uncorrected unless noted otherwise.

PREPARATION OF INTERMEDIATES EXAMPLE 1

A. A solution of 76 g. (0.6 mole) of benzyl chloride in 450 ml. of diethyl ether was added to a mixture of 14.6 g. (0.6 moles) of magnesium turnings in 150 ml. of dry ether at such a rate as to maintain gentle reflux. The resulting solution was then added by filtration through glass wool to a suspension of 75 g. (0.3 mole) of 4-ethylpyridine methiodide in 150 ml. of ether. The mixture was stirred for three hours at room temperature, poured into a mixture of ice/water containing ammonium chloride, and the organic layer was separated, dried, filtered, and diluted with ether to a volume of 900 ml.

The solution containing 1-methyl-2-benzyl-4-ethyl-1,2-dihydropyridine was divided into three 300 ml. portions, and each portion was evaporated to dryness, dissolved, respectively, in 200 ml. portions of benzene, toluene and xylene, and the three separate solutions treated with 22 ml. of ethyl acrylate and refluxed overnight. The solutions were each allowed to cool, diluted with diethyl ether and extracted with 150 ml. of 1N hydrochloric acid. The combined extracts were washed once with diethyl ether, then basified with 15 ml. of concentrated ammonium hydroxide and the mixtures each extracted with 150 ml. of diethyl ether. The extracts of the three samples afforded, respectively, 18.2 g., 20.0 g. and 19.3 g. of product as oils. The three samples were dissolved in diethyl ether and acidified with ethereal hydrochloric acid to give a total of 32.2 g. of ethyl 2-methyl-3-benzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride, m.p. 189°-191° C.

Following a procedure similar to that described in Example 1A, using either benzene, toluene or xylene as solvent, an appropriate 4-R₂ -3-R₂ '-2-R₂ '''-benzylmagnesium chloride of formula VI, an appropriate 3-R₃ -4-R₄ -1-R₁ -pyridinium halide of formula VII and an appropriate dienophile, CH₂ ═CHY', the following 2-R₁ -3-(4-R₂ -3-R₂ '-2-R₂ '''-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-enes of formula IV are prepared. Unless noted otherwise, the products were isolated and characterized in the form of the hydrochloride salt. The anion of the quaternary of formula VII is given in parentheses along with the weight of VII used.

Here and elsewhere throughout this specification in subsequent tables, the weights of starting materials (S.M.) and products (Prod.) are given in grams in the appropriate columns headed "Wt. ----", and melting points of the final products, together with the solvent of recrystallization, are given in the last column.

Where weights of only one of several reactants are given, the weights of such other reactants can be calculated on a proportionate molar basis from the amounts used in the example referred to for the preparative procedure employed. In some instances, the products were neither characterized nor purified, either by distillation or recrystallization, but rather were used directly in the next step as isolated from the reaction mixture.

The particular form of the starting material or product, whether base or salt, is specified along with the weights by use of designations such as "base", "HCl", "HBr", etc. to indicate that the weights are given, respectively, for the free base or the hydrochloride, hydrobromide, etc. salts.

                                      Table 1a                                     __________________________________________________________________________     Example                                                                             R.sub.1 /Y'                                                                            R.sub.2 /R.sub.2 '                                                                  R.sub.3 /R.sub.4                                                                       Wt.VII/Wt.IV                                                                           m.p. (° C.)/Solv.                     __________________________________________________________________________     1B   C.sub.6 H.sub.5 CH.sub.2                                                               H    H       23.4 (Cl.sup.-)                                                                        196 - 199                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        15.3    ethanol/ether                                1C   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          H       117 (Cl.sup.-)                                                                         183 - 186                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        76      ethanol/ether                                1D   CH.sub.3                                                                               CH.sub.3 O                                                                          H       124 (I.sup.-)                                                                          - 204                                             COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        76      ethanol/ether                                1E   CH.sub.3                                                                               H    H       117 (I.sup.-)                                                                          237 - 238                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               57      ethanol/ether                                1F   C.sub.6 H.sub.5 CH.sub.2                                                               H    H       109.9 (Cl.sup.-)                                                                       215 - 217                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               114.9   ethanol/ether                                1G   C.sub.6 H.sub.5 CH.sub.2                                                               H    H       117 (Cl.sup.-)                                                                         106 - 111.sup.(a)                                 COCH.sub.3                                                                             H    C.sub.2 H.sub.5                                                                        43.7    ethanol                                      1H   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          H       154 (Cl.sup.-)                                                                         216- 219                                          COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               120     ethanol/ether                                1J   CH.sub.3                                                                               H    CH.sub.3                                                                               75.9 (I.sup.-)                                                                         168 - 170                                         COCH.sub.3                                                                             H    C.sub.2 H.sub.5                                                                        26.8    ethanol/ether                                1K   CH.sub.3                                                                               H    CH.sub.3                                                                               50 (I.sup.-)                                                                           174                                               COCH.sub.3                                                                             H    CH.sub.3                                                                               19.3    ethanol/ether                                1L   CH.sub.3                                                                               H    CH.sub.3                                                                               37.4 (I.sup.-)                                                                         240 - 241.sup.(b)                                 CN      H    CH.sub.3                                                                               17      ethanol                                      1M   CH.sub.3                                                                               CH.sub.3 O                                                                          H       165 (I.sup.-)                                                                          200 - 202.sup.(c)                                 COOCH.sub.3                                                                            H    CH.sub.3                                                                               58.8    ethanol/acetone                              1N   C.sub.6 H.sub.5 CH.sub.2                                                               H    H       165 (Cl.sup.-)                                                                         165 - 170.sup.(d)                                 COCH.sub.3                                                                             H    CH.sub.3                                                                               123.1   ethanol/ether                                1P   CH.sub.3                                                                               H    H       27.9 (I.sup.-)                                                                         146 - 149                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.2 CH.sub.2 OCH.sub.3                                                            6.4     ethanol/ether                                1Q   C.sub.3 H.sub.5 -CH.sub.2.sup.(e)                                                      H    H       11.6 (Br.sup.-)                                                                        230                                               COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               8.6     ethanol                                      1R   CH.sub.3                                                                               H    H       184 (I.sup.-)                                                                          171 - 174                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.3 H.sub.7                                                                        71.3    ethanol/ether                                1S   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          H       112 (Cl.sup.-)                                                                         125 - 130                                         COCH.sub.3                                                                             H    CH.sub.3                                                                               64.5    ethanol/ether                                1T   C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               11.7 (Cl.sup.-)                                                                        218 - 220                                         COOC.sub.2 H.sub.5 (g)                                                                 H    CH.sub.3                                                                               6.1     ethanol/ether                                1U   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          CH.sub.3                                                                               157 (Cl.sup.-)                                                                         146                                               COCH.sub.3                                                                             H    CH.sub.3                                                                               15.3    ethanol/ether                                1V   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          H       165 (Cl.sup.-)                                                                         122 - 127                                         COCH.sub.3                                                                             H    C.sub.2 H.sub.5                                                                        105.3   acetone                                      1W   C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               238 (I.sup.-)                                                                          166 - 168                                         COCH.sub.3                                                                             H    C.sub.2 H.sub.5                                                                        36.3    ethanol/ether                                1X   C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               46.8 (Cl.sup.-)                                                                        oil                                               COCH.sub.3                                                                             H    CH.sub.3                                                                               54                                                   1Y   CH.sub.3                                                                               H    H       40.0 (I.sup.-)                                                                         127 - 129.sup.(f)                                 COOC.sub.2 H.sub.5                                                                     H    CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5                                                     37      acetone                                      1Z   C.sub.6 H.sub.5 CH.sub.2                                                               H    C.sub.2 H.sub.5                                                                        172 (I.sup.-)                                                                          204 - 208                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               54      ethanol/ether                                1AA  CH.sub.3                                                                               H    CH.sub.3                                                                               149     188 - 190                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        109     ethanol/ether                                1AB  CH.sub.3                                                                               CH.sub.3 O                                                                          CH.sub.3                                                                               148     186 - 188                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        46      ethanol/ether                                1AC  C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               33.9    214 - 217                                         COOC.sub.2 H.sub.5                                                                     H    C.sub.2 H.sub.5                                                                        5.5     ethanol/ether                                1AD  CH.sub.3                                                                               H    H       94      167 - 169                                         COOC.sub.2 H.sub.5                                                                     H    H       2.7     ethanol/ether                                1AE  C.sub.6 H.sub.5 CH.sub.2                                                               H    H       25.3    201 - 203                                         COOC.sub.2 H.sub.5                                                                     H    H       0.9     ethanol/ether                                1AF  CH.sub.3                                                                               H    CH.sub.3                                                                               50      215 - 218                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               27.5    ethanol/ether                                1AG  C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                          CH.sub.3                                                                               200     208 - 210                                         COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               31.5    --                                           1AH  C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               285 (Cl.sup.-)                                                                         203 - 212                                         COOC.sub.2 H.sub.5                                                                     CH.sub.3 O                                                                          CH.sub.3                                                                               120.7   acetone/ether                                1AJ  C.sub.6 H.sub.5 CH.sub.2                                                               H    CH.sub.3                                                                               11.9 (Cl.sup.-)                                                                        229.5 - 232.5                                     COOC.sub.2 H.sub.5                                                                     CH.sub.3 O.sup.(h)                                                                  CH.sub.3                                                                               6.0     ethanol/ether                                1AK  CH.sub.3                                                                               CH.sub.3 O                                                                          CH.sub.3                                                                               121.3 (Br.sup.-)                                                                       191.0 - 201.0.sup.(f)                             COOC.sub.2 H.sub.5                                                                     H    CH.sub.3                                                                               70.1                                                 1AL  CH.sub.3                                                                               CH.sub.3 O                                                                          --(CH.sub.2).sub.4.sup.--                                                              19.0 (I.sup.-)                                                                         181 - 183                                         COOC.sub.2 H.sub.5                                                                     H            10.6    ethanol/ether                                __________________________________________________________________________      .sup.(a) Free base                                                             .sup.(b) Hydrochloride hemiethanolate                                          .sup.(c) The corresponding ethyl ester hydrochloride prepared similarly        using ethyl acrylate as the dienophile has m.p. 205-206° C. (from       ethanol).                                                                      .sup.(d) The free base has m.p. 118-120° C. (from isopropanol).         .sup.(e) Cyclopropylmethyl                                                     .sup.(f) Oxalate. The free base has m.p. 67-68° C. (from pentane).      .sup.(g) The carboxylic acid (47 g.), m.p. 191-196° C. (free base)      was prepared by saponification of the ester (58.5 g.)                          .sup.(h) CH.sub.3 O group in 2-position.                                 

EXAMPLE 1AM

A solution of 21.2 g. (0.05 mole) of the ethyl 2,3-dibenzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride described above in Example 1B was dissolved in a solution of 100 ml. of 1N sodium hydroxide and 100 ml. of ethanol, and the solution was heated and stirred under reflux for four hours. The ethanol was then removed in vacuo, the mixture diluted with water and then acidified with glacial acetic acid. Extraction of the mixture with chloroform afforded 21.1 g. of a gummy material which was dissolved in methanol and treated with an excess of methanesulfonic acid. The solid which separated on dilution with diethyl ether was collected to give 15.1 g. of 2,3-dibenzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylic acid methanesulfonate, m.p. 220°-222° C.

EXAMPLE 1AN

A solution of 10 g. (0.02 mole) of ethyl 2-benzyl-3-(4-methoxybenzyl)-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride described above in Example 1H in 100 ml. of absolute ethanol was reduced with hydrogen over 1.0 g. of 10% palladium-on-charcoal, and when reduction was complete, the catalyst was removed by filtration and the filtrate taken to dryness. The residue was recrystallized from ethanol/ether to give 7.0 g. of ethyl 3-(4-methoxybenzyl)-5-methyl-2-azabi-cyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride, m.p. 173°-175° C., which on further recrystallization gave material having m.p. 177°-179° C.

Following a procedure similar to that described in Example 1AN above, the following compounds of formula IV were prepared, where in each case R₁, R₂, R₂ ', R₂ " and R₂ ''' are hydrogen; R₄ is CH₃ and Y' is COOC₂ H₅. Both compounds were isolated and characterized as the hydrochloride salt.

                  Table 1b                                                         ______________________________________                                         Example R.sub.3 Wt.S.M./Wt.Prod.                                                                              m.p. (° C.)/Solvent                      ______________________________________                                         1AP     CH.sub.3                                                                               42.6           223 - 226                                                       24.2           ethanol/ether                                   1AQ     H       34.0           160 - 162                                                       20.1           acetone                                         ______________________________________                                    

Following a procedure similar to that described in Example 1A, using an appropriate 4-R₂ -3-R₂ '-2-R₂ '''-benzylmagnesium chloride of formula VI, an appropriate 3-R₃ -4-R₄ -1-R₁ -pyridinium halide of formula VII and methyl vinyl ketone as dienophile, the following 2-R₁ -3-(4-R₂ -3-R₂ '-2-R₂ "-benzyl)-4-R₃ -5-R₄ -7-CH₃ CO-2-azabicyclo[2.2.2]oct-5-enes of formula IV are prepared, where in each case Y' is COCH₃ and R₂ ''' is hydrogen.

                                      Table 1c                                     __________________________________________________________________________     Example                                                                             R.sub.1      R.sub.2 /R.sub.2 '                                                                     R.sub.3 /R.sub.4                                     __________________________________________________________________________     1AR  CH.sub.3     H       H                                                                      Cl      CH.sub.3                                             1AS  CH.sub.3     H       H                                                                      Br      CH.sub.3                                             1AT  CH.sub.3     H       H                                                                      F       CH.sub.3                                             1AU  CH.sub.3     H       H                                                                      CF.sub.3                                                                               CH.sub.3                                             1AV  CH.sub.3     H       H                                                                      CH.sub.3                                                                               CH.sub.3                                             1AW  CH.sub.3     C.sub.6 H.sub.5                                                                        H                                                                      H       CH.sub.3                                             1AX  CH.sub.3                                                                                     ##STR31##                                                                             H CH.sub.3                                           1AY  CH.sub.3     H       H                                                                      H       H                                                    1AZ  CH.sub.3     H       H                                                                      H       CH.sub.2 CH.sub.2 l                                  1BA  CH.sub.3     H       (CH.sub.2).sub.3                                                       H                                                            1BB  CH.sub.3     H       (CH.sub.2).sub.4                                                       H                                                            1BC  C.sub.6 H.sub.11                                                                            CH.sub.3 S                                                                             H                                                                      H       CH.sub.3                                             1BD  4-BrC.sub.6 H.sub.4 H.sub.2 CH.sub.2                                                        CH.sub.3 O                                                                             H                                                                      H       CH.sub.3                                             1BE  4-C1C.sub.6 H.sub.4 CH.sub.2 H.sub.2                                                        CH.sub.3 CONH                                                                          H                                                                      H       CH.sub.3                                             1BF  4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        C.sub.2 H.sub. 5 OCONH                                                                 H                                                                      H       CH.sub.3                                             1BG  4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                           H       H                                                                      H       CH.sub.3                                             1BH  3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                             H       H                                                                      H       CH.sub.3                                             1BJ  3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                    H       H                                                                      H       CH.sub.3                                             1BK  4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H       H                                                                      H       CH.sub.3                                             1BL  3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                H       H                                                                      H       CH.sub.3                                             1BM  3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H       H                                                                      H       H.sub.3                                              1BN                                                                                  ##STR32##   H H     H CH                                                 1BP  CH.sub.3     H       H                                                                      H       CH.sub.2 CH.sub.2 SCH.sub.3                          __________________________________________________________________________

EXAMPLE 1BQ

Reduction of the ethyl 2,3-dibenzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylic described in Example 1AE in the form of the hydrochloride salt with one molar equivalent of hydrogen over a palladium-on-charcoal catalyst at ambient temperature and reaction of the resulting ethyl 3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate with acetyl chloride in the presence of pyridine affords ethyl 2-acetyl-3-benzyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate.

EXAMPLE 2

A. A mixture of 12.3 g. (0.035 mole) of the ethyl 2-methyl-3-benzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride, described above in Example 1A, in 125 ml. of 48% aqueous hydrobromic acid was stirred under reflux for twenty-four hours and cooled. The solid which separated was collected to give 8.4 g. of 1-methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide, m.p. 290°-293° C., which on recrystallization from water gave material having m.p. 295°-299° C.

Following a procedure similar to that described in Example 2A, using an appropriate 2-R₁ -3-(4-R₂ -benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-ene of formula IV, the following 7-R₂ -1-R₁ -3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines of formula II are prepared where, unless noted otherwise, R₂ ', R₂ ", R₂ ''' and R₈ in each case are hydrogen. The cyclization can be carried out using hydrofluoric acid at 0°-15° C., concentrated sulfuric acid at ambient temperature, or hydrobromic acid in glacial acetic acid at reflux temperature. The particular acid used to promote reaction in each case is identified below by the designations HF, H₂ SO₄ and HBr, as the case may be. Unless noted otherwise the products were isolated as the hydrochloride salts.

                                      Table 2a                                     __________________________________________________________________________     Example                                                                             R.sub.1 /Y                                                                            R.sub.2                                                                             R.sub.3 /R.sub.4                                                                       Wt.IV/Wt.II                                                                           m.p. (° C.)/Solv.                       __________________________________________________________________________     2B   C.sub.6 H.sub.5 CH.sub.2                                                              H    H       42.6   258 - 260                                      HBr  COOH.sup.(a)                                                                               C.sub.2 H.sub.5                                                                        11.5   ethanol/ether                                  2C   CH.sub.3                                                                              HO   H       58.1   293.sup.(c)                                    HBr  COOH.sup.(b)                                                                               C.sub.2 H.sub.5                                                                        30.2   H.sub.2 O                                      2D   CH.sub.3                                                                              H    H       50     269.sup.(c)                                    HBr  COOH.sup.(a)                                                                               CH.sub.3                                                                               36.7   ethanol/ether                                  2E   C.sub.6 H.sub.5 CH.sub.2                                                              H    H       10     109 - 111.sup.(d)                              H.sub.2 SO.sub.4                                                                    COCH.sub.3  C.sub.2 H.sub.5                                                                        7.1    methanol                                       2F   C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O                                                                          H       10     225 - 228                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               7.3    acetone                                        2G   CH.sub.3                                                                              H    CH.sub.3                                                                               10     99 - 103.sup.(d)                               H.sub.2 SO.sub.4                                                                    COCH.sub.3  C.sub.2 H.sub.5                                                                        3.7    hexane                                         2H   CH.sub.3                                                                              HO.sup.(e)                                                                          H       45.0   283 - 284                                      HBr  COOCH.sub.3 CH.sub.3                                                                               17.6   ethanol                                        2J   CH.sub.3                                                                              H    H       88.4   228 - 229                                      HBr  COOC.sub. 2 H.sub.5                                                                        C.sub.3 H.sub.7                                                                        23.3   isopropanol                                    2K   C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O                                                                          H       5.0    126 - 129.sup.(d)                              HF   COCH.sub.3  CH.sub.3                                                                               2.6    ethanol                                        2L   C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O                                                                          H       176    88 - 90.sup.(d)                                HF   COCH.sub.3  C.sub.2 H.sub.5                                                                        43.2   ethanol                                        2M   CH.sub.3                                                                              CH.sub.3 O                                                                          H       153.7  101 - 102.sup.(d)                              HF   COOC.sub.2 H.sub.5.sup.(f)                                                                 CH.sub.3                                                                               94.6   ethyl acetate                                  2N   C.sub.6 H.sub.5 CH.sub.2                                                              H    CH.sub.3                                                                               200    207 - 209                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               167    ethanol/ether                                                                  88 - 90.sup.(d)                                2P   C.sub.6 H.sub.5 H.sub.2                                                               CH.sub.3 O                                                                          CH.sub.3                                                                               4.3    125 ∝ 126.sup.(d)                       HF   COCH.sub.3  CH.sub.3                                                                               3.2    ethanol                                        2Q   C.sub.6 H.sub.5 CH.sub.2                                                              H    CH.sub.3                                                                               79.2   95 - 98.sup.(d)                                HF   COCH.sub.3  C.sub.2 H.sub.5                                                                        29.3   ethanol                                        2R   C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O                                                                          H       0.5    244 - 246                                      HF   COOC.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                        0.25   ethanol/ether                                  2S   C.sub.6 H.sub.5 CH.sub.2                                                              H    H       66     200 - 203                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               53     ethanol/ether                                  2T   C.sub.6 H.sub.5 CH.sub.2                                                              H    H       10     136 - 138.sup.(d)                              H.sub.2 SO.sub.4                                                                    COCH.sub.3  CH.sub.3                                                                               3      ethanol                                        2U   CH.sub.3                                                                              H    H       1.0    189 - 191                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.2 CH.sub.2 OCH.sub.3                                                            0.85   ethanol/ether                                  2V   CH.sub.3                                                                              H    H       10     185 - 189                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5                                                     5.6    acetone                                        2W   CH.sub.3                                                                              H    CH.sub.3                                                                               11.1   225 - 227                                      HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               9.2    acetone                                        2X   CH.sub.3                                                                              H    CH.sub.3                                                                               10.9   202 - 205                                      H.sub.2 SO.sub.4                                                                    COOC.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                        5.9    acetonitrile/                                                                  ether                                          2Y   C.sub.6 H.sub.5 CH.sub.2                                                              H    CH.sub.3                                                                               33.7   82 - 83.sup.(d)                                H.sub.2 SO.sub.4                                                                    COOC.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                        21.4   hexane                                         2Z   C.sub.6 H.sub.5 CH.sub.2                                                              H    C.sub.2 H.sub.5                                                                        75     213 -  215                                     H.sub.2 SO.sub.4                                                                    COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               29     ethanol/ether                                  2AA  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O                                                                          CH.sub.3                                                                               314.5  98 - 100.sup.(d)                               HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               137.9                                                 2AB  CH.sub.3                                                                              CH.sub.3 O                                                                          CH.sub.3                                                                               21.7   98 - 101                                       HF   COOC.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                        16.1   ethanol                                        2AC  C.sub.6 H.sub.5 H.sub.2                                                               CH.sub.3 O.sup.(g)                                                                  CH.sub.3                                                                               94     123 - 124.sup.(d,h)                            HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               31.4.sup.(h)                                                                          ethanol                                        2AD  C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3 O.sup.(j)                                                                  CH.sub.3                                                                               73.5   207.0 - 209.5                                  HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               48.2   ethanol/ether                                  2AE  CH.sub.3                                                                              CH.sub.3 O                                                                          CH.sub.3                                                                               60.3   93.0 - 94.0.sup.(d)                            HF   COOC.sub.2 H.sub.5                                                                         CH.sub.3                                                                               36.3   ethanol                                        2AF  CH.sub.3                                                                              CH.sub.3 O                                                                          --(CH.sub.2).sub.4 --                                                                  6.6    oil                                            HF   COOC.sub.2 H.sub.5  4.7                                                   __________________________________________________________________________      .sup.(a) Starting material was the ethyl ester.                                .sup.(b) Starting material was the methoxy ether/ethyl ester.                  .sup.(c) Hydrobromide salt                                                     .sup.(d) Free base                                                             .sup.(e) Starting material was the methoxy ether/methyl ester.                 .sup.(f) 100 g. of the ester was saponified with aqueous alkali and the        product isolated as the free base to give 55.7 g. of the corresponding         carboxylic acid, m.p. 195 - 197° C. (acetonitrile).                     .sup.(g) Prepared from compound of Example 1AH. CH.sub.3 O group is in th      8-position.                                                                    .sup.(h) Yield and m.p given for 8-methoxy isomer. An additional 16.3 g.       of isomeric 6-methoxy hydrochloride obtained, m.p. 226 - 227° C.        (ethanol/ether).                                                               .sup.(j) Prepared from the compound of Example 1AJ. CH.sub.3 O group is i      the 9-position.                                                          

EXAMPLE 2AG

A solution of 4.2 g. (0.01 mole) of ethyl 1-methyl-5α-[2-(phenylthio)ethyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate described in Example 2V in 80 ml. of glacial acetic acid was treated with 1.4 ml. of 30% aqueous hydrogen peroxide, allowed to stand at ambient temperature for one hour and fifteen minutes and then concentrated to dryness in vacuo at 40° C. The residue was partitioned between dilute sodium hydroxide and methylene dichloride and the organic layer separated, dried and taken to dryness to give 5.0 g. of ethyl 1-methyl-5α-[2-(phenylsulfinyl)ethyl]-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate as an oil.

The latter (14.0 g., 0.032 mole) was distilled under reduced pressure, and the fraction boiling at 122°-156° C./0.03-0.11 mm. was collected (7 g.) and chromatographed on silica in a 6:4 solution of hexane:ether. The column was eluted until the yellow color passed through, and the next 550 ml. was collected separately and taken to dryness to give 6.4 g. of a gum which was dissolved in anhydrous ether and diluted with ethereal hydrogen chloride. The solid which separated was collected and dried to give 3.8 g. of ethyl 1-methyl-5α-vinyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride, m.p. 241°-243° C.

The latter (2.1 g., 0.006 mole) was converted to the free base which was dissolved in 15 ml. of tetrahydrofuran and treated with 15.6 ml. of a 1M solution of diborane in tetrahydrofuran. The solution was stirred for an hour and a half, poured into 10 ml. of ice water, the mixture basified with 3.6 ml. of 3N sodium hydroxide and treated with 2.2 ml. of 30% hydrogen peroxide. After stirring for an hour, the mixture was filtered, diluted with water, extracted with ether and the ether extracts extracted with dilute hydrochloric acid. Isolation of the basic product from the aqueous acid medium in the usual manner by basifying and extraction with ether and conversion of the product to the hydrochloride salt gave ethyl 1-methyl-5α-(2-hydroxyethyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride, m.p. 212°-216° C. (from acetone).

Following a procedure similar to that described in Example 2A, using an appropriate 2-R₁ -3-(4-R₂ -3-R₂ '-benzyl)-4-R₃ -5-R₄ -7-Y'-2-azabicyclo[2.2.2]oct-5-ene of formula IV and hydrofluoric acid at 0°-15° C., the following 7-R₂ -8-R₂ '-1-R₁ -3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methano-benzo[g]quinolines of formula II, where R₂ ", R₂ ''' and R₈ in each case are hydrogen, are prepared.

                                      Table 2b                                     __________________________________________________________________________     Example                                                                             R.sub.1 /Y    R.sub.2 /R.sub.2 '                                                                     R.sub.3 /R.sub.4                                    __________________________________________________________________________     2AH  C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                             H                                                        COOC.sub.2 H.sub.5                                                                           H       CH.sub.3                                            2AJ  CH.sub.3      H       CH.sub.3                                                 COCH.sub.3    H       CH.sub.3                                            2AK  CH.sub.3      H       CH.sub.3                                                 CN            H       CH.sub.3                                            2AL  cyclopropyl-CH.sub.2                                                                         H       H                                                        COOC.sub.2 H.sub.5                                                                           H       CH.sub.3                                            2AM  CH.sub.3      H       H                                                        COCH.sub.3    Cl      CH.sub.3                                            2AN  CH.sub.3      H       H                                                        COCH.sub.3    Br      CH.sub.3                                            2AP  CH.sub.3      H       H                                                        COCH.sub.3    F       CH.sub.3                                            2AQ  CH.sub.3      H       H                                                        COCH.sub.3    CF.sub.3                                                                               CH.sub.3                                            2AR  CH.sub.3      H       H                                                        COCH.sub.3    CH.sub.3                                                                               CH.sub.3                                            2AS  CH.sub.3      C.sub.6 H.sub.5                                                                        H                                                        COCH.sub.3    H       CH.sub.3                                            2AT  CH.sub.3 COCH.sub.3                                                                           ##STR33##                                                                             H CH.sub.3                                          2AU  CH.sub.3      H       H                                                        COCH.sub.3    H       H                                                   2AV  CH.sub.3      H       H                                                        COCH.sub.3    H       CH.sub.2 CH.sub.2 Cl                                2AW  CH.sub.3 COCH.sub.3                                                                          H H                                                                                     ##STR34##                                          2AX  CH.sub.3 COCH.sub.3                                                                          H H                                                                                     ##STR35##                                          2AY  C.sub.6 H.sub.11                                                                             CH.sub.3 S                                                                             H                                                        COCH.sub.3    H       CH.sub.3                                            2AZ  4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        CH.sub.3 O                                                                             H                                                        COCH.sub.3    H       CH.sub.3                                            2BA  4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        CH.sub.3 CONH                                                                          H                                                        COCH.sub.3    H       CH.sub.3                                            2BB  4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                         C.sub.2 H.sub.5 OCONH                                                                  H                                                        COCH.sub.3    H       CH.sub.3                                            2BC  4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                            H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BD  3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BE  3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                     H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BF  4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BG  3-CF.sub.3 C.sub.6 H.sub.4 H.sub.2 CH.sub.2                                                  H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BH  3-CH.sub.3 CONHC.sub.6 H.sub. 4 CH.sub.2 CH.sub.2                                            H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BJ                                                                                  ##STR36##    H       H                                                        COCH.sub.3    H       CH.sub.3                                            2BK  CH.sub.3      H       H                                                        COCH.sub.3    H       CH.sub.2 CH.sub.2 SCH.sub.3                         __________________________________________________________________________

EXAMPLE 2BL

Cyclization of 2,5-dimethyl-3-(3-methylbenzyl)-7-acetyl-2-azabicyclo[2.2.2]oct-5-ene, described in Example 1AV, in the presence of hydrofluoric acid at 0°-15° C. using a procedure similar to that described above in Example 2A affords 1,5α,6-trimethyl-3-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline.

EXAMPLE 2BM

Cyclization of ethyl 2-acetyl-3-benzyl-2-azabicyclo-[2.2.2]oct-5-ene-7-carboxylate, described in Example 1BQ, in the presence of hydrofluoric acid at 0°-15° C. using a procedure similar to that described in Example 2A affords ethyl 1-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.

EXAMPLE 3

A solution containing 21.3 g. (0.05 mole) of ethyl 2,3-dibenzyl-5-ethyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride (described in Example 1B) in 200 ml. of ethanol was reduced over 2.1 g. of palladium-on-charcoal using the procedure described above in Example 1AN. There was thus obtained 18 g. of ethyl 3-benzyl-5-ethyl-2-azabicyclo[2.2.2]-oct-5-ene-7-carboxylate which, without further purification, was dissolved in 170 ml. of 48% hydrobromic acid and heated under reflux for about eight hours. The crude product obtained was recrystallized from water to give 9.4 g. of 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide, m.p. > 310° C.

EXAMPLE 4

A. A mixture of 48.3 g. (0.13 mole) of 1-methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide (described in Example 2A) in 480 ml. of absolute ethanol was treated with anhydrous hydrogen chloride until all material had dissolved. The solution was refluxed for three hours, taken to dryness, and the solid residue was partitioned between dilute ammonium hydroxide and diethyl ether. The ether layer was separated, combined with additional ether washes of the aqueous layer, and the combined organic extracts dried and evaporated to dryness. The resulting solid residue was dissolved in ethanol and treated with ethereal hydrogen chloride to give 39.3 g. of ethyl 1-methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride, m.p. 244°-246° C.

Following a procedure similar to that described in Example 4A, using an appropriate 7-R₂ -1-R₁ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide of formula II and an appropriate lower-alkanol, the corresponding lower-alkyl esters of formula II given in Table 4 below are prepared, where R₂ ', R₂ ", R₂ '" and R₈ in each case are hydrogen. Unless noted otherwise, melting points are given for the free base form.

                  Table 4                                                          ______________________________________                                                                     Wt. Acid/                                                                               m.p.(° C.)/                        Ex.  R.sub.1 /Y                                                                               R.sub.2                                                                               R.sub.3 /R.sub.4                                                                     Wt.Prod. Solv.                                     ______________________________________                                         4B   CH.sub.3  H      H     10.3     129 - 133                                      COOCH.sub.3      CH.sub.3                                                                             5.0      methanol                                  4C   H         H      H     11.2     245 - 246.sup.(a)                              COOC.sub.2 H.sub.5                                                                              C.sub.2 H.sub.5                                                                      8.0      ethanol/ether                             4D   CH.sub.3  HO     H     10.0     190 - 193                                      COOCH.sub.3      C.sub.2 H.sub.5                                                                      5.4      ethyl acetate/                                                                 hexane                                    4E   C.sub.6 H.sub.5 CH.sub.2                                                                 H      CH.sub.3                                                                             18.1     .sup.(b)                                       COOC.sub.3 H.sub.7                                                                              CH.sub.3                                                                             --                                                 ______________________________________                                          .sup.(a) Hydrochloride salt                                                    .sup.(b) Not isolated but treated further in Example 6D. Acid (50.3 g.)        obtained by saponification of 77.9 g. of compound of Example 2N.         

EXAMPLE 5

A. A solution of 53.7 g. (0.15 mole) of 1-benzyl-3-acetyl-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline (described in Example 2K) in 250 ml. of 48% aqueous hydrobromic acid was warmed on a steam bath for 2 hours and then filtered and cooled. The solid which had precipitated was collected and recrystallized from water to give 10.3 g. of 1-benzyl-3-acetyl-5α-methyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrobromide, m.p. 192°-197° C.

Following a procedure similar to that described in Example 5A, using an appropriate 6-, 8- or 9-methoxy-3-Y-4 aα,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formula II, the corresponding 6-, 8- or 9-hydroxy compounds of formula II in Table 5 below were prepared, the position of the hydroxy group (R₂, R₂ ', R₂ " or R₂ '") being given in the column headed "R₂ Posn.". In each case R₁ is hydrogen, and R₃ and R₄ are both methyl. The compounds were prepared from the hydrochloride salts and, unless indicated otherwise, were isolated as the methanesulfonates.

                  Table 5                                                          ______________________________________                                                                 Wt.S.M./                                               Ex.  Y         R.sub.2 Posn.                                                                           Wt.Prod.  m.p. (° C.)/Solv.                     ______________________________________                                         5B   COOC.sub.2 H.sub.5                                                                       8-HO     6.2       275 - 277                                                            2.8       ethanol                                      5C   COOC.sub.2 H.sub.5                                                                       6-HO     7.0       219 - 221                                                            3.2       acetone                                      5D   COOC.sub.2 H.sub.5                                                                       9-HO     16.5      255 - 257.sup.(a)                                                    2.4.sup.(a)                                                                              ethanol/ether                                ______________________________________                                          .sup.(a)Hydrochloride salt                                               

EXAMPLE 6

A. A solution of 21.7 g. (0.06 mole) of 1-benzyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline (described in Example 2E) in 100 ml. of ethanol was made acidic with aqueous hydrochloric acid, and the solution was reduced with hydrogen over 2.0 g. of 10% palladium-on-charcoal at room temperature using a Parr shaking apparatus. When reduction was complete, the catalyst was removed by filtration, the filtrate concentrated to dryness in vacuo, and the residue recrystallized from isopropanol to give 14.4 g. of 3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 240°-241° C.

Following a procedure similar to that described in Example 6A, using an appropriate 6-R₂ "-7-R₂ -8-R₂ '-9-R₂ '"-1-benzyl-3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formula II, the corresponding debenzylated compounds of formula II in Table 6 below were prepared, where R₁ and R₈ in each case are hydrogen. The position of the R₂, R₂ ', R₂ " or R₂ '" group when other than hydrogen is given in the column headed "R₂ Posn.". The compounds were prepared from, and isolated as, either the hydrobromide, the hydrochloride or the free base as indicated.

                                      Table 6                                      __________________________________________________________________________     Example                                                                             Y     R.sub.2 Posn.                                                                       R.sub.3 /R.sub.4                                                                   Wt.S.M./Wt.Prod.                                                                         m.p. (° C.)/Solv.                         __________________________________________________________________________     6B   COCH.sub.3                                                                           7-HO H   8.2 (HBr) 247 - 248                                                        CH.sub.3                                                                           4.8 (HBr) acetonitrile                                     6C   COOC.sub.2 H.sub.5                                                                   --   CH.sub.3                                                                           42.6 (HCl)                                                                               213 - 216                                                        CH.sub.3                                                                           26.4 (HCl)                                                                               ethanol/ether                                    6D   COOC.sub.3 H.sub.7                                                                   --   CH.sub.3                                                                           .sup.(a)  213 - 215                                                        CH.sub.3                                                                           13.6 (HCl)                                                                               acetonitrile                                     6E   COOC.sub.2 H.sub.5                                                                   --   CH.sub.3                                                                           16.1 (base)                                                                              226 - 229                                                        C.sub.2 H.sub.5                                                                    9.0(HCl)  ethanol/ether                                    6F   COOC.sub.2 H.sub.5                                                                   --   H   18.8 (base)                                                                              213 - 214                                                        CH.sub.3                                                                           11.9 (HCl)                                                                               ethanol/ether                                    6G   COOC.sub.2 H.sub.5                                                                   --   C.sub.2 H.sub.5                                                                    22.0 (HCl)                                                                               150 - 151                                                        CH.sub.3                                                                           12.6 (HCl)                                                                               ether                                            6H   COOCH.sub.3.sup.(b)                                                                  --   CH.sub.3                                                                           15.0 (base).sup.(b)                                                                      221 - 223                                                        CH.sub.3                                                                           7.5 (HCl) ethanol/ether                                    6J   COOC.sub.2 H.sub.5                                                                   7-CH.sub.3 O                                                                        CH.sub.3                                                                           21.0 (base)                                                                              202 - 203                                                        CH.sub.3                                                                           14.2 (HCl)                                                                               acetone/ether                                    6K   COOC.sub.2 H.sub.5                                                                   7-HO.sup.(c)                                                                        CH.sub.3                                                                           21.0 (base)                                                                              185 -  187                                                       CH.sub.3                                                                           8.0 (base)                                                                               ethyl acetate                                    6L   COOC.sub.2 H.sub.5                                                                   8-CH.sub.3 O                                                                        CH.sub.3                                                                           15.0 (base)                                                                              226 - 228                                                        CH.sub.3                                                                           11.2 (HCl)                                                                               acetone                                          6M   COOC.sub.2 H.sub.5                                                                   6-CH.sub.3 O                                                                        CH.sub.3                                                                           16.3 (HCl)                                                                               227 - 228                                                        CH.sub.3                                                                           10.3 (HCl)                                                                               acetone                                          6N   COOC.sub.2 H.sub.5                                                                   9-CH.sub.3 O                                                                        CH.sub.3                                                                           20.0 (HCl)                                                                               261 - 262                                                        CH.sub.3                                                                           13.3 (HCl)                                                                               ethanol/ether                                    __________________________________________________________________________      .sup.(a) Reaction carried out on product of Example 4E without isolation       of the latter.                                                                 .sup.(b) Prepared by saponification of 61.1 g. of the compound of Example      2N (36.9 g. of free base of the carboxylic acid, m.p. 178 - 185° C      obtained) and reesterification of the acid with methanol. Debenzylation        carried out on the product directly without isolation.                         .sup.(c) The crude product, without isolation, was cleaved with boiling        48% hydrobromic acid using the procedure described in Example 5.         

EXAMPLE 7

A. A mixture of 5.0 g. (0.017 mole) of ethyl 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride (described in Example 4C), 2.8 g. (0.17 mole) of cyclopropylmethyl bromide and 1.4 g. (0.017 mole) of sodium bicarbonate in 40 ml. of DMF was stirred and refluxed for three hours, and then evaporated to dryness in vacuo. The residue was partitioned between water and diethyl ether, the ether layer was washed with water, dried, charcoaled and filtered, and the filtrate was diluted with ethanol and acidified with ethereal hydrogen chloride. The solid which separated was collected and recrystallized from ethanol/ether to give 4.4 g. of ethyl 1-cyclopropylmethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride, m.p. 215°-217° C.

Following a procedure similar to that described in Example 7A, using an appropriate alkylating agent and an appropriate 3-Y-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline, the following compounds of formula II in Table 7 were prepared, where in each case, unless noted otherwise, R₂, R₂ ', R₂ ", R₂ '" and R₈ are each hydrogen. The form of the starting materials and the products, whether free base or a particular salt form, is indicated in each case.

    ______________________________________                                                                   Wt.S.M./  m.p.(° C.)/                         Ex.  R.sub.1 /Y   R.sub.3 /R.sub.4                                                                       Wt.Prod.  Solv.                                      ______________________________________                                         7B   cyclopropyl-CH.sub.2                                                                        H       27.6 (HCl)                                                                               202 - 204                                       COCH.sub.3   C.sub.2 H.sub.5                                                                        24.1 (HCl)                                                                               ethanol/ether                              7C   C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                           CH.sub.3                                                                               11.3 (base)                                                                              173 - 174                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               5.9 (CH.sub.3 SO.sub.3 H)                                                                ethyl acetate/                                                                 ether                                      7D   C.sub.2 H.sub.5                                                                             CH.sub.3                                                                               11.0 (HCl)                                                                               218 - 219                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               7.4 (HCl) acetone                                    7E   n-C.sub.3 H.sub.7                                                                           CH.sub.3                                                                               11.0 (HCl)                                                                               210 - 213                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               8.7 (HCl) acetone                                    7F   n-C.sub.4 H.sub.9                                                                           CH.sub.3                                                                               11.0 (HCl)                                                                               213 - 216                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               7.2 (HCl) acetone                                    7G   n-C.sub.5 H.sub.11                                                                          CH.sub.3                                                                               11.0 (HCl)                                                                               200 - 203                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               7.8 (HCl) acetone                                    7H   CH.sub.2 CHCH.sub.2                                                                         CH.sub.3                                                                               6.0 (base)                                                                               120 - 123                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               5.3 (HCl) acetone                                    7J   CH.sub.2 CHC(CH.sub.3).sub.2                                                                CH.sub.3                                                                               8.6 (base)                                                                               196 - 199                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               7.8 (HCl) acetone                                    7K   cyclopropyl-CH.sub.2                                                                        CH.sub.3                                                                               7.5 (base)                                                                               213 - 215                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               6.2 (HCl) acetone                                    7L   CH.sub.2 C.tbd.CH                                                                           CH.sub.3                                                                               7.5 (base)                                                                               184 - 186                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               5.8 (HCl) ethanol/ether                              7M   cyclobutyl-CH.sub.2                                                                         CH.sub.3                                                                               6.6 (base)                                                                               217 - 219                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               1.2 (HCl) acetone                                    7N   3-furyl-CH.sub.2                                                                            CH.sub.3                                                                               7.5 (base)                                                                               213 - 215                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               5.5 (HCl) ethanol                                    7P   CH.sub.3.sup.(a)                                                                            CH.sub.3                                                                               27.6 (base)                                                                              235 - 238                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               14.5 (HCl)                                                                               ethanol/ether                              7Q   CH.sub.3.sup.(a)(b)                                                                         CH.sub.3                                                                               9.0 (base)                                                                               200 - 202                                       COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               2.7 (HCl) acetone/ether                              7R   CH.sub.3.sup.(a)(c)                                                                         CH.sub.3                                                                               20.5 (base)                                                                              98 - 100                                        COOC.sub.2 H.sub.5                                                                          CH.sub.3                                                                               22.9 (base)                                                                              hexane                                     ______________________________________                                          .sup.(a) Prepared by warming the starting material of formula II with a        molar excess each of formic acid and 37% aqueous formaldehyde.                 .sup.(b) Product is ethyl                                                      1,3,4aα,5α-tetramethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-meth     nobenzo[g]quinoline-3-carboxylate prepared from the 3-methyl-3-carboxylate      described in Example 17.                                                       .sup.(c) R.sub.2 is CH.sub.3 O.                                          

EXAMPLE 7S

Debenzylation of the ethyl 1-benzyl-4aα,5α-dimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate described above in Example 2AA using the procedure described above in Example 6A and alkylation of the resulting ethyl 4aα,5α-dimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with cyclopropylmethyl bromide in DMF in the presence of sodium carbonate using the procedure described above in Example 7A affords ethyl 1-cyclopropylmethyl-4aα,5α-dimethyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.

EXAMPLE 8

A. A mixture of 18.0 g. (0.05 mole) of 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide (described in Example 3), 20.4 g. (0.11 mole) of β-phenylethyl bromide and 13.5 g. (0.16 mole) of sodium bicarbonate in 200 ml. of DMF was stirred under reflux for 4 hours, and then worked up in the manner described above in Example 7A. The crude product was converted to the hydrochloride salt which was recrystallized from isopropanol to give 4.4 g. of 2-phenylethyl 1-(2-phenylethyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate hydrochloride, m.p. 237°-238° C.

B. Following a procedure similar to that described in Example 8A, 20.5 g. (0.058 mole) of 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid hydrobromide (described in Example 3) was reacted with 19.8 g. (0.12 mole) of cyclopropylmethyl bromide in the presence of sodium bicarbonate, and the product converted to the hydrochloride salt which was recrystallized from ethanol/ether to give 6.6 g. of cyclopropylmethyl 1-cyclopropylmethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylate hydrochloride, m.p. 184°-187° C.

EXAMPLE 9

A. A solution of 0.035 mole of ethyl 1-methyl-5α-propyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (obtained from 14.4 g. of the corresponding hydrochloride described above in Example 2J) in diethyl ether was added in a fine stream to 81 ml. of a 2.16M solution (0.175 mole) of methyl lithium in diethyl ether. When addition was complete, the mixture was stirred for about thirty minutes, allowed to stand overnight, and then poured into an ice/aqueous ammonium chloride mixture. The ether layer was separated, the aqueous layer washed with diethyl ether, and the combined organic extracts washed with saturated brine, dried, filtered, and concentrated to dryness. The residue was dissolved in ethanol/ether, and the solution acidified with ethereal hydrogen chloride. The solid which separated was collected and recrystallized from ethanol/ether to give 2.5 g. of 1-methyl-3-(2-hydroxy-2-propyl)-5α-propyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 257°-258° C.

Following a procedure similar to that described in Example 9A, using an appropriate lower-alkyl 7-R₂ -1-R₁ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate of formula II described in Examples 4A, 4B, 4D, 8A, 2M, 7A and 2N, respectively, and methyl lithium, the following compounds of formula II in Table 9, where in each case Y is C(CH₃)₂ OH and R₂ ', R₂ ", R₂ '" and R₈ are hydrogen, are prepared. In each case, the weights of starting materials are given for the free base form, and unless noted otherwise, melting points of the products are given for the hydrochloride salt.

                  Table 9                                                          ______________________________________                                                                       Wt.                                                                            S.M./Wt.                                                                              m.p.(° C.)/                        Ex.  R.sub.1    R.sub.2 R.sub.3 /R.sub.4                                                                     Prod.  solv.                                     ______________________________________                                         9B   CH.sub.3   H       H     15.7   275                                                               C.sub.2 H.sub.5                                                                      6.9    ethanol                                   9C   CH.sub.3   H       H     15     256 - 257                                                         CH.sub.3                                                                             12.2   ethanol/ether                             9D   CH.sub.3   HO      H     12.9   272                                                               C.sub.2 H.sub.5                                                                      8.1    ethanol/ether                             9E   C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                         H       H     8.2    248 - 248.5                                                       C.sub.2 H.sub.5                                                                      3.9    ethanol/ether                             9F   CH.sub.3   CH.sub.3 O                                                                             H     25     126 - 127.sup.(a)                                                 CH.sub.3                                                                             22.1   hexane                                    9G   C.sub.3 H.sub.5 --CH.sub.2.sup.(b)                                                        H       H     6.1    256                                                               C.sub.2 H.sub.5                                                                      4.5    ethanol/ether                             9H   H.sup.(c)  H       CH.sub.3                                                                             13.7   152 - 153.sup.(a)                                                 CH.sub.3                                                                             4.4    isopropyl                                                                      acetate/hexane                            ______________________________________                                          .sup.(a) Free base                                                             .sup.(b) Cyclopropylmethyl                                                     .sup.(c) Product debenzylated without isolation using the procedure of         Example 6A.                                                              

EXAMPLE 10

A. To a suspension of 44.1 g. (0.16 mole) of 1-methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]-quinoline-3-carboxylic acid (from the hydrobromide described in Example 2A) in 390 ml. of diethyl ether was added in a fine stream 230 ml. (0.5 mole) of a 2.16M solution of methyl lithium in diethyl ether. When addition was complete, the mixture was stirred for 3 hours, poured into an ice/aqueous ammonium chloride solution, and worked up in the manner described in Example 9A. There was thus obtained 32.8 g. of product as an oily crude base, 3.3 g. of which was converted to the hydrochloride salt. The latter was recrystallized from methanol/diethyl ether to give 2.3 g. of 1-methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 191° C.

Following a procedure similar to that described in Example 10A, using an appropriate 7-R₂ -1-R₁ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid of formula II described in Examples 2A, 2C, 2M, 2F and 2AA and an appropriate organo lithium, R₅ Li, the following compounds of formula II in Table 10a were prepared, where in each case R₂ ', R₂ ", R₂ '" and R₈ are hydrogen. The form (salt or base) of the starting material is given in each case in parentheses along with the weight or starting material, and, of course, salt forms were converted to the free base before reaction with the organo lithium. The melting points for the compounds of Examples 10B and 10D are given for the hydrochloride salts and for the free base of the compounds of Examples 10C, 10E, 10H and 10J.

                                      Table 10a                                    __________________________________________________________________________     Example                                                                             R.sub.1 /COR.sub.5                                                                     R.sub.2                                                                            R.sub.3 / R.sub.4                                                                  Wt.S.M./Wt.Prod.                                                                         m.p. (° C.)/Solv.                        __________________________________________________________________________     10B  CH.sub.3                                                                               H   H   12.1 (base)                                                                              190 - 191                                            COC.sub.3 H.sub.7                                                                          C.sub.2 H.sub.5                                                                    8.0 (HCl) isopropanol/ether                               10C  CH.sub.3                                                                               HO  H   36 (HBr)  201 - 204                                            COCH.sub.3  C.sub.2 H.sub.5                                                                    18.9 (base)                                                                              DMF/H.sub.2 O                                   10D  CH.sub.3                                                                               H   H   8.6 (base)                                                                               200 - 202                                            COC.sub.6 H.sub.5                                                                          C.sub.2 H.sub.5                                                                    6.4 (HCl) ethanol/ether                                   10E  CH.sub.3                                                                               CH.sub.3 O                                                                         H   18 (base) 65 - 67                                              COCH.sub.5 H.sub.11                                                                        CH.sub.3                                                                           6.3 (base)                                                                               ethanol                                         10F  C.sub.6 H.sub.5 CH.sub.2                                                               H   CH.sub.3                                                                           59.8 (base)                                                                              --                                                   COCH.sub.3  CH.sub.3                                                                           55.3 (base)                                                                              --                                              10G  CH.sub.3                                                                               CH.sub.3 O                                                                         CH.sub.3                                                                           27.8 (base)                                                                              130                                                  C(OH)(C.sub.5 H.sub.11).sub.2                                                              CH.sub.3                                                                           2.3 (HCl) acetone/ether                                        (.sup.a)                                                                  10H  C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                         H   60 (HC1).sup.(b)                                                                         146 - 151                                            COC(CH.sub.3).sub.3                                                                        CH.sub.3                                                                           25.2 (base)                                                                              ethanol                                         10J  C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3 O                                                                         CH.sub.3                                                                           4.2 (base).sup.(b)                                                                       112- 115                                             COC(CH.sub.3).sub.3                                                                        CH.sub.3                                                                           1.6 (base)                                                                               ethanol                                         __________________________________________________________________________      .sup.(a) Product isolated was result of reaction of three moles of amyl        lithium per mole of carboxylic acid, i.e. 1,4aα,                         5α-trimethyl-7-methoxy-3-(6-hydroxy-6-undecyl)-1,2,3,4,4a,5,10,10a-     ctahydro-2,5-methanobenzo[g]quinoline hydrochloride.                            .sup.(b) Starting material was ethyl 3-carboxylate ester.                

Following a procedure similar to that described in Example 10A, using an appropriate 7-R₂ -1-R₁ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid (prepared by alkaline saponification of the corresponding esters described above) and an appropriate lower-alkyl or cycloalkyl-lower-alkyl lithium, the following compounds of formula II in Table 10b are prepared where, in each case, R₂ ', R₂ ", R₂ '" and R₈ are each hydrogen.

                  Table 10b                                                        ______________________________________                                         Example                                                                               R.sub.1 /Y     R.sub.2 R.sub.3 /R.sub.4                                 ______________________________________                                         10K    CH.sub.3       H       H                                                       COCH.sub.3             CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5               10L    CH.sub.3       H       H                                                       COCH.sub.3             CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5              10M    CH.sub.3       H       H                                                       COCH.sub.3             CHCH.sub.2                                       10N    CH.sub.3       H       H                                                       COCH.sub.3             CH.sub.2 CH.sub.2 OH                             10P    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 CH.sub.3    CH.sub.3                                         10Q    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 CH.sub.3                                                                           CH.sub.3                                         10R    C.sub.3 H.sub.5 CH.sub.2                                                                      CH.sub.3l O                                                                            CH.sub.3                                                CO(CH.sub.2).sub.3 CH.sub.3                                                                           CH.sub.3                                         10S    CH.sub.3       CH.sub.3 O                                                                             H                                                       CO(CH.sub.2).sub.3 CH.sub.3                                                                           CH.sub.3                                         10T    C.sub.6 H.sub.5 CH                                                                            CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.3 CH.sub.3                                                                           CH.sub.3                                         10U    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 CH(CH.sub.3).sub.2                                                                         CH.sub.3                                         10V    C.sub.6 H.sub.5 CH.sub.2                                                                      H       CH.sub.3                                                CO(CH.sub.2).sub.4 CH.sub.3                                                                           CH.sub.3                                         10W    C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.4 CH.sub.3                                                                           CH.sub.3                                         10X    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                                 CH.sub.3                                         10Y    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.5 CH.sub.3                                                                           CH.sub.3                                         10Z    CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 -cyclopropyl                                                                               CH.sub.3                                         10AA   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 -cyclopropyl                                                                       CH.sub.3                                         10AB   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 -cyclobutyl CH.sub.3                                         10AC   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 -cyclobutyl                                                                        CH.sub.3                                         10AD   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 -cyclopentyl                                                                               CH.sub.3                                         10AE   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 -cyclopentyl                                                                       CH.sub.3                                         10AF   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                COCH.sub.2 -cyclohexyl CH.sub.3                                         10AG   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 -cyclohexyl                                                                        CH.sub.3                                         10AH   CH.sub.3       CH.sub.3 O                                                                             CH.sub. 3                                               CO(CH.sub.2).sub.3 CH.sub.3                                                                           CH.sub.3                                         10AJ   CH.sub.3       CH.sub.3 O                                                                             CH.sub.3                                                CO(CH.sub.2).sub.2 C.sub.6 H.sub.5                                                                    CH.sub.3                                         10AK   CH.sub.3 CO    H       H                                                       CO(CH.sub.2).sub.3 CH.sub.3                                                                           H                                                ______________________________________                                    

EXAMPLE 11

A. A solution of 2.8 g. (0.01 mole) of 1-methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline (from the hydrochloride described in Example 10A) in 25 ml. of diethyl ether was added dropwise to a solution of 40 ml. (0.032 mole) of a 0.8M solution of propyl lithium in diethyl ether. When addition was complete, the mixture was allowed to stand for one hour, poured into an ice/aqueous ammonium chloride solution and worked up in the manner described in Example 9A. The product thus obtained was converted to the hydrochloride salt which was recrystallized from ethanol/ether to give 1.2 g. of 1-methyl-3-(2-hydroxy-2-pentyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 227°-230° C. (designated isomer A).

B. The compound, 1-methyl-3-(2-hydroxy-2-pentyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline, m.p. 103°-105° C. (from hexane) (the hydrochloride salt shows m.p. 263°-265° C., from isopropanol/DMF), isomeric in the configuration of the 3-(2-hydroxy-2-pentyl) group with isomer A above and designated isomer B, was prepared in a similar fashion by reaction of 1-methyl-3-butyryl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline (from the hydrochloride salt described in Example 10B) with methyl lithium.

Following a procedure similar to that described in Example 11A, using an appropriate 7-R₂ -1-R₁ -3-acetyl-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Examples 2G and 2K, respectively, and methyl lithium, the following compounds of formula II in Table 11 were prepared where, in each case, Y is C(CH₃)₂ OH and R₂ ', R₂ ", R₂ '" and R₈ are each hydrogen. All melting points are for the hydrochloride salts.

                  Table 11                                                         ______________________________________                                                                     Wt. S.M./                                                                               m.p. (° C.)/                       Ex.  R.sub.1  R.sub.2 R.sub.3 /R.sub.4                                                                     Wt. Prod.                                                                               Solv.                                     ______________________________________                                         11C  CH.sub.3 H       CH.sub.3                                                                             5.0 (base)                                                                              247-248                                                         C.sub.2 H.sub.5                                                                      4.4      ethanol/ether                             11D  C.sub.6 H.sub.5 CH.sub.2                                                                CH.sub.3 O                                                                             H     15.0 (base)                                                                             236-237                                                         CH.sub.3                                                                             12.2     ethanol/ether                             ______________________________________                                    

EXAMPLE 12

A. A solution of 0.076 mole of ethyl 1-methyl-5α-ethyl-1,2,3,4,4a,5,10, 10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (obtained from 26.7 g. of the hydrochloride salt described in Example 4A) in 250 ml. of anhydrous diethyl ether was added in a fine stream to a stirred suspension of 2.9 g. (0.076 mole) of lithium aluminum hydride in 125 ml. of diethyl ether. When addition was complete, the mixture was stirred for about one hour, treated dropwise with 5.8 ml. of water, stirred for an additional ten minutes, and then filtered through filter aid. The filter cake was washed with several portions of diethyl ether, and the combined filtrates were evaporated to dryness to give 20.8 g. of the product in the form of the free base, 7.0 g. of which was dissolved in 35 ml. of ethanol and acidified with ethereal hydrogen chloride. The solid which separated was collected and recrystallized from ethanol/diethyl ether to give 7.6 g. of 1-methyl-3-hydroxymethyl-5α-ethyl-1,2,3,4,4 a,5,10, 10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 273°-278° C.

Following a procedure similar to that described in Example 12A using the ethyl 1-methyl-4aα,5α-dimethyl-1,2,3, 4, 4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates described in Examples 7P, 2W and 7Q, respectively, there were obtained the following compounds of formula II where in each instance R₁, R₃ and R₄ are each CH₃ and R₂ , R₂ ', R₂ " and R₂ ''' are each hydrogen. The products were isolated and characterized as the hydrochloride salts.

                  Table 12                                                         ______________________________________                                                              Wt. S.M./  m.p. (° C.)/                            Example                                                                               Y/R.sub.8     Wt. Prod.  Solv.                                          ______________________________________                                         12B    CH.sub.2 OH (Isomer A)                                                                       10.5 (base)                                                                               245-247                                               H             7.5        ethanol/ether                                  12C    CH.sub.2 OH (Isomer B)                                                                       13.4 (base)                                                                               270-274                                               H             10.6       ethanol/ether                                  12D    CH.sub.2 OH   3.8 (base) 232-234                                               CH.sub.3      2.5        ethanol/ether                                  ______________________________________                                    

EXAMPLE 13

A solution of 8.5 g. (0.3 mole) of 1-methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride (described in Example 10A) in 135 ml. of ethanol was added in a fine stream to a solution of 1.2 g. (0.03 mole) of sodium borohydride in 25 ml. of ethanol. When addition was complete, the mixture was stirred for 4 1/4 hours and then decanted from the precipitated solids. The liquid layer was evaporated to dryness, the residue dissolved in dilute hydrochloric acid and the solution basified with concentrated ammonium hydroxide. Extraction of the mixture with diethyl ether afforded 7.5 g. of crude base which was converted to the hydrochloride salt to give 3.3 g. of 1-methyl-3-(1-hydroxyethyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro2,5-methanobenzo[g]quinoline hydrochloride, m.p. 305°-307° C.

Following a procedure similar to that described in Example 13A, using the lower-alkyl 1-R₁ -4aα-R₃ -5α-R₄ -7-R₂ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylates described in Examples 2M and 6D, respectively, there were obtained the following compounds of formula II where R₂ ', R₂ ", R₂ ''' and R₈ in each case is hydrogen. The compounds were prepared from the free bases and the products isolated and characterized either as the free base of the hydrochloride salt as indicated.

                  Table 13                                                         ______________________________________                                                                     Wt. S.M./                                                                               m.p. (° C)/                        Ex.  R.sub.1 /Y                                                                              R.sub.2 R.sub.3 /R.sub.4                                                                     Wt. Prod.                                                                               Solv.                                     ______________________________________                                         13B  CH.sub.3 CH.sub.3 O                                                                             H     25.0     264-268                                        CH.sub.2 OH      CH.sub.3                                                                             21.4 (HC1)                                                                              ethanol/ether                             13C  H        H       CH.sub.3                                                                             15.2     165-166                                        CH.sub.2 OH      CH.sub.3                                                                             3.7 (base)                                                                              isopropyl ace-                                                                 tate/hexane                               ______________________________________                                    

EXAMPLE 14

A. A solution of 4.8 g. (0.018 mole) of 1-methyl-3-hydroxymethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride (described in Example 12A) in 50 ml. of pyridine was treated with 4.8 g. (0.02 mole) of 3,4,5-trimethoxybenzoyl chloride, the solution heated on a steam bath for six and one half hours and then allowed to stand overnight. The solid material which had separated was collected and recrystallized from ethanol/ether to give 7.1 g. of 1-methyl-3-(3,4,5-trimethoxybenzoyloxymethyl)-5α-ethyl-1,2,3, 4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 247°-249° C.

B. Following a procedure similar to that described in Example 14A, using 7.9 g. (0.029 mole) of the 1-methyl-3-hydroxymethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 12A and 80 ml. of propionic anhydride, and isolation of the product in the form of the hydrochloride salt, there was obtained 3.9 g. of 1-methyl-3-propionyloxymethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride, m.p. 264°-266° C. (from ethanol/ether).

Following a procedure similar to that described in Example 14A using the 1-methyl-3-hydroxymethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 12A and an appropriate acid chloride in the presence of pyridine, the following compounds of formula II described in Table 14 are prepared where, in each instance, R₁ is CH₃ ; R₂, R₂ ', R₂ ", R₂ ''', R₃ and R₈ are hydrogen; R₄ is C₂ H₅ ; and Y is CH₂ OR₇.

                  Table 14                                                         ______________________________________                                         Example          R.sub.7                                                       ______________________________________                                         14C              4-CH.sub.3 C.sub.6 H.sub.4 CO                                 14D              4-HOC.sub.6 H.sub.4 CO                                        14E              3-C1C.sub.6 H.sub.4 CO                                        14F              3-BrC.sub.6 H.sub.4 CO                                        14G              3-FC.sub.6 H.sub.4 CO                                         14H              3-CF.sub.3 C.sub.6 H.sub.4 CO                                 ______________________________________                                    

EXAMPLE 15

A. A solution of 427 g. (0.97 mole) of ethyl 2-benzyl-3-(4-methoxybenzyl)-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride (described in Example 1H) was dissolved in 1800 ml. of ethanol and reduced in two portions with hydrogen over 10 g. of palladium-on-charcoal. The product was worked up in the manner described above in Example 1AN to give 273 g. of ethyl 3-(4-methoxybenzyl)-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate.

The latter was dissolved in 700 ml. of dry ethanol, and the solution added to a solution of 11 g. (0.48 mole) of sodium dissolved in 2 liters of dry ethanol. The resulting solution was stirred and refluxed for 72 hours, treated with 39 ml. of glacial acetic acid, cooled to room temperature and filtered through filter aid. The solution was evaporated to dryness, the solid residue was refluxed with ethyl acetate, the mixture was filtered, and the filtrate diluted with hexane to give one crop of 75 g. of product, m.p. 130° C. The filtrate, on extraction with dilute mineral acid, evaporation to dryness and recrystallization of the residue from ethyl acetate/hexane gave an additional 23 g. of product (total yield 98 g.), 2-(4-methoxybenzyl)-8-methylene-3-azabicyclo[3.3.1]non-6-en-4-one. A small sample, recrystallized twice from ethyl acetate/hexane, gave material having m.p. 132°-133° C.

B. Following a procedure similar to that described in Example 15A, catalytic debenzylation of the ethyl 2,3-dibenzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride described in Example 1F and base catalyzed rearrangement of the resulting ethyl 3-benzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate affords 2-benzyl-8-methylene-3-azabicyclo[3.3.1]non-6-en-4-one.

EXAMPLE 16

To a solution of 0.15 mole of sodium ethoxide (prepared by dissolving 3.5 g. of sodium in 250 ml. of absolute ethanol) was added 28.5 g. (0.095 mole) of ethyl 4aα,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (described above in Example 6C), and the solution was stirred and refluxed for about 8 hours, then neutralized by the addition of 8.6 ml. of glacial acetic acid, evaporated to dryness, and the residue dissolved in 200 ml. of water and 200 ml. of dilute hydrochloric acid. The aqueous solution was washed twice with ether, basified by the addition of about 30 ml. of concentrated ammonium hydroxide, and extracted twice with ether. The combined ether extracts, on washing with water, then with saturated sodium chloride, drying, filtering and evaporation to dryness, afforded 23.8 g. of a syrup which was dissolved in absolute ethanol, and treated with ethanolic hydrogen chloride. The solid which separated was removed by filtration, and the filtrate evaporated to dryness to give a residue which was dissolved in 200 ml. of water. The solution was washed once with ether, then basified by the addition of concentrated ammonium hydroxide, and extracted two times with diethyl ether. The ether extracts on washing, drying, filtering and evaporation to dryness afforded 19.0 g. of a solid which was dissolved in 100 ml. of ethyl acetate and treated with a solution of 12.1 g. of p-toluenesulfonic acid monohydrate in 200 ml. of ethyl acetate. There was thus obtained a solid which was recrystallized from ethanol/ether to give 7.0 g. of ethyl 4aα,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate p-toluenesulfonate, m.p. 216°-220° C., isomeric at the 3-position with the starting material.

EXAMPLE 17

To a solution of 30 ml. of 2.0M butyl lithium in hexane was added with cooling in an external ice bath a solution of 8.4 g. of cyclohexylisopropylamine (0.06 mole) in 45 ml. of pentane. When addition was complete, the solution was evaporated to dryness, and the resulting gum was dissolved in 60 ml. of tetrahydrofuran and the solution cooled to -70° C. with a dry ice/acetone bath. The solution was then treated with a solution of 11.7 g. of ethyl 1-benzyl-4aα,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate (described in Example 2N) in 120 ml. of tetrahydrofuran. When addition was complete the solution was stirred at -70° C. for about thirty minutes, allowed to warm to -20° C., and then treated with a solution of 12.8 g. (0.09 mole) of methyl iodide in 120 ml. of dimethylsulfoxide. The solution was stirred at ambient temperature for 1 hour and then poured into one liter of cold water and extracted three times with 200 ml. of ether. The ether extracts on washing with water and brine and evaporation to dryness afforded 17.5 g. of a yellow oil which was chromatographed in 10% ether/hexane on a column of 2 kg. of silica. The product was eluted with 10% ether/hexane, the first 4.7 liters of eluate being discarded. The next 2 liters were combined and evaporated to dryness to give 3.13 g. of crude ethyl 1-benzyl-3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate.

The latter was dissolved in 200 ml. of absolute ethanol containing 0.7 ml. of concentrated hydrochloric acid, 0.5 g. of 10% palladium-on-charcoal was added, and the mixture was reduced under about 50 p.s.i. of hydrogen using the procedure described above in Example 6A. The product was converted to the methanesulfonate salt which was recrystallized from ethanol/ether to give 2.0 g. of ethyl 3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate methanesulfonate, m.p. 225°-229° C.

Reaction of the above-described ethyl 1-benzyl-3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate with one mole of methyl lithium using the procedure described in Example 10A affords 1-benzyl-3-acetyl-3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline.

Preparation of Final Products EXAMPLE 18

A. A solution of 11 g. (0.039 mole) of 1-methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride (described in Example 10A) in 20 ml. of a solution prepared by adding 89 ml. of trimethylamine to 94 ml. of formic acid was stirred and heated under reflux for about 15 minutes. The mixture was allowed to cool, diluted with 100 ml. of water and washed with 50 ml. of diethyl ether. The aqueous layer was basified with 15 ml. of concentrated ammonium hydroxide and extracted twice with diethyl ether. The combined organic extracts, on washing once with water, drying and concentration to dryness, afforded 10 g. of a solid residue which was dissolved in about 30 ml. of absolute ethanol, the solution acidified with 13 ml. of ethereal hydrogen chloride, and diluted to 250 ml. with additional ether. The solid which separated was collected, washed, and set aside. (See Example 31A). The filtrate was washed with dilute ammonium hydroxide, dried, filtered and taken to dryness to give 3.1 g. of residue which was dissolved in diethyl ether and acidified with ethereal hydrogen chloride. The gummy, semi-crystalline material which separated was recrystallized from ethanol/ether to give 0.8 g. of 6(eq)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 192°-196° C.

B. An alternative method for the preparation of the compounds of formula I from the compounds of formula II is illustrated by the following procedure:

A mixture of 10.0 g. (0.03 mole) of 1-methyl-3-acetyl-5α-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 10C in 675 ml. of mesitylene and 25 ml. of formic acid was stirred and refluxed for about 8 hours while adding additional formic acid from time to time in order to maintain the pot temperature at 117°-119° C. The mixture was then cooled, extracted with dilute hydrochloric acid and the acid extracts washed first with diethyl ether, then basified with ammonium hydroxide and extracted once again with ethyl acetate. The organic extracts, on washing with brine, drying and evaporation to dryness, afforded 8.4 g. of solid which was recrystallized from ethyl acetate to give 3.7 g. of 6(eq)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-8-hydroxy-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine, m.p. 190°-192° C.

Following a procedure similar to that described in Example 18A or B above, using an appropriate 7-R₂ -1-R₁ -3-COR₅ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formula II, the following 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-(oxo-lower-alkyl)-2,6-methano-3-benzazocines of formula I in Table 18a are prepared, where R₂ ', R₂ ", R₂ ''' and R₈ in each case are hydrogen. The particular procedure used, that of Example 18A or 18B, is indicated by the letter designation (A) or (B), respectively, below the Example number. Unless noted otherwise, products were isolated as, and melting points recorded for, the free base form.

                                      Table 18a                                    __________________________________________________________________________                                     m.p. (° C.)/                            Ex.                                                                               R.sub.1 /CH.sub.2 Z                                                                           R.sub.2                                                                            R.sub.3 /R.sub.4                                                                   Wt.II/Wt.I                                                                           Solv.k                                         __________________________________________________________________________     18C                                                                               CH.sub.3       H   CH.sub.3                                                                           10 (base)                                                                            207-208 (a)                                    (A)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      C.sub.2 H.sub.5                                                                    2.1 (salt)                                                                           ethanol/ether                                                            (a)                                                  18D                                                                               C.sub.3 H.sub.5 -CH.sub.2 (c)                                                                 H   H   16 (base)                                                                            206-208 (b)                                    (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      C.sub.2 H.sub.5                                                                    7.8 (base)                                                                           ethanol/ether                                  18E                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         H   18.8 (base)                                                                          104-106                                        (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      CH.sub.3                                                                           7.2 (base)                                                                           ethanol                                        18F                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         H   39 (base)                                                                            122-125                                        (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      C.sub.2 H.sub.5                                                                    10.6 (base)                                                                          ethanol                                        18G                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         CH.sub.3                                                                           19.5 (base)                                                                          132-135                                        (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      CH.sub.3                                                                           11.5 (base)                                                                          ethanol                                        18H                                                                               CH.sub.3       CH.sub.3 O                                                                         H   4.9 (base)                                                                           132-134                                        (B)                                                                               CH.sub.2 CH.sub.2 COC.sub.5 H.sub.11                                                              CH.sub.3                                                                           3.3 (salt)                                                                           ethanol/ether                                                            (d)                                                  18J                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      H   CH.sub.3                                                                           55.3 (base)                                                                          229-232                                        (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.3                                                                      CH.sub.3                                                                           37.7 (HC1)                                                                           ethanol/ether                                  18K                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         H   18.7 (base)                                                                          244-246                                        (B)                                                                               CH.sub.2 CH.sub.2 COC(CH.sub.3).sub.3                                                             CH.sub.3                                                                           15.3 (HC1)                                                                           ethanol/ether                                  18L                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         CH.sub.3                                                                           39.2 (base)                                                                          248-255                                        (B)                                                                               CH.sub.2 CH.sub.2 COC(CH.sub.3).sub.3                                                             CH.sub.3                                                                           33.0 HC1)                                                                            ethanol/ether                                  18M                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  217-221                                        (B)                                                                               CH.sub.2 CH.sub.2 COCH.sub.2 CH.sub.3                                                             CH.sub.3                                                                           salt (e)                                                                             ethanol/ether                                  18N                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  176-179                                        (B)                                                                               CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH.sub.3                                                 CH.sub.3                                                                           salt (e)                                                                           acetone/ether                                        18P                                                                               C.sub.3 H.sub.5 -CH.sub.2 (c)                                                                 CH.sub.3 O                                                                         CH.sub.3                                                                           base  219-220                                        (B)                                                                               CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                 CH.sub.3                                                                           HC1 acetone                                              18Q                                                                               CH.sub.3       CH.sub.3 O                                                                         H   base  183.5-185                                      (B)                                                                               CH.sub.2 CH.sub.2 CO(CH.sub. 2).sub.3 CH.sub.3                                                CH.sub.3                                                                           salt (f)                                                                           acetone                                              18R                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         CH.sub.3                                                                           base  226-228                                        (B)                                                                               CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                 CH.sub.3                                                                           HC1 acetone                                              18S                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  146-148                                           CH.sub.2 CH.sub.2 COCH.sub.2 CH(CH.sub.3).sub.2                                               CH.sub.3                                                                           salt (e)                                                                           acetone/ether                                        18T                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      H   CH.sub.3                                                                           base  190-193                                           CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                                 CH.sub.3                                                                           HC1 acetone/ether                                        18U                                                                               C.sub.6 H.sub.5 CH.sub.2                                                                      CH.sub.3 O                                                                         CH.sub.3                                                                           base  226-227                                           CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.4 CH.sub.3                                                 CH.sub.3                                                                           HC1 acetone/ether                                        18V                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  29-231                                            CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                       CH.sub.3                                                                           HC1 acetone                                              18W                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  178-181 (g)                                       CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.5 CH.sub.3                                                 CH.sub.3                                                                           HC1 acetone/ether                                        18X                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  oil                                               CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 CH(CH.sub. 3).sub.2                                      CH.sub.3                                                                           base                                                     18Y                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  209-212                                           CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.3 CH.sub.3                                                     CH.sub.3                                                                           HC1   ethanol/ether                                  18Z                                                                               CH.sub.3       CH.sub.3 O                                                                         CH.sub.3                                                                           base  137-141                                           CH.sub.2 CH.sub.2 CO(CH.sub.2).sub.2 C.sub.6 H.sub.5                                              CH.sub.3                                                                           HBr.H.sub.2 O                                                                        H.sub.2 O                                      __________________________________________________________________________      (a) p-Toluenesulfonate hemihydrate                                             (b) Hydrochloride                                                              (c) Cyclopropylmethyl                                                          (d) p-Toluenesulfonate                                                         (e) Methanesulfonate                                                           (f) Picrate                                                                    (g) The p-toluenesulfonate has m.p. 188-190° C. (from acetone)    

Following a procedure similar to that described in Example 18A or 18B above, using an appropriate 7-R₂ -8-R₂ '-1-R₁ -3-lower-alkanoyl-4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline of formula II, there are obtained the following 8-R₂ -9-R₂ '-6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocines of formula I in Table 18b, where in each case R₂ ", R₂ ''' and R₈ are each hydrogen.

                                      Table 18b                                    __________________________________________________________________________     Example                                                                               R.sub.1 /CH.sub.2 Z                                                                           R.sub.2 /R.sub.2 '                                                                       R.sub.3 /R.sub.4                               __________________________________________________________________________     18AA   C.sub.6 H.sub.5 CH.sub.2                                                                      H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         C.sub.2 H.sub.5                                18AB   CH.sub.3       H         CH.sub.3                                              CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AC   C.sub.6 H.sub.5 CH.sub.2                                                                      H         H                                                     CH.sub.2 CH.sub.2 COCO.sub.3                                                                  H         CH.sub.3                                       18AD   C.sub.6 H.sub.5 CH.sub.2                                                                      HO        H                                                     CH.sub.2 CH.sub.2 COCO.sub.3                                                                  H         CH.sub.3                                       18AE   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COC.sub.3 H.sub.7                                                           H         C.sub.2 H.sub.5                                18AF   C.sub.6 H.sub.11                                                                              CH.sub.3 S                                                                               H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AG   4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                         CH.sub.3 O                                                                               H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AH   4-C1C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                         CH.sub.3 CONH                                                                            H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AJ   4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                          C.sub.2 H.sub.5 OCONH                                                                    H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AK   4-C1-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                             H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AL   3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AM   3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                      H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AN   4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                 H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AP   3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                  H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AQ   3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AR                                                                                   ##STR37##     H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AS   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  Cl        CH.sub.3                                       18AT   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  Br        CH.sub.3                                       18AU   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  F         CH.sub.3                                       18AV   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  CF.sub.3  CH.sub.3                                       18AW   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  CH.sub.3  CH.sub.3                                       18AX   CH.sub.3       C.sub.6 H.sub.5                                                                          H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.3                                       18AY   CH.sub.3                                                                                       ##STR38##                                                                               H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                            CH.sub.3                                       18AZ   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         H                                              18BA   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 Cl                           18BB   CH.sub.3       H                                                                                         ##STR39##                                            CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H                                                        18BC   CH.sub.3       H                                                                                         ##STR40##                                            CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H                                                        18BD   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 OCH.sub.3                    18BE   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COC.sub.6 H.sub.5                                                           H         C.sub.2 H.sub.5                                18BF   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5             18BG   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5            18BH   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH═CH.sub.2                                18BJ   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 SCH.sub.3                    18BK   CH.sub.3       H         H                                                     CH.sub.2 CH.sub.2 COCH.sub.3                                                                  H         CH.sub.2 CH.sub.2 OH                           18BL   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              COCH.sub.2 -cyclopropyl                                                                       H         CH.sub.3                                       18BM   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              CO(CH.sub.2).sub.2 -cyclopropyl                                                               H         CH.sub.3                                       18BN   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              COCH.sub.2 -cyclobutyl                                                                        H         CH.sub.3                                       18BP   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              CO(CH.sub.2).sub.2 -cyclobutyl                                                                H         CH.sub.3                                       18BQ   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              COCH.sub.2 -cyclopentyl                                                                       H         CH.sub.3                                       18BR   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              CO(CH.sub. 2).sub.2 -cyclopentyl                                                              H         CH.sub.3                                       18BS   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                       18BS   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              COCH.sub.2 -cyclohexyl                                                                        H         CH.sub.3                                       18BT   CH.sub.3       CH.sub.3 O                                                                               CH.sub.3                                              CO(CH.sub.2).sub.2 -cyclohexyl                                                                H         CH.sub.3                                       __________________________________________________________________________

EXAMPLE 18BU

Heating the 1,5α,8-trimethyl-3-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 2AR with formic acid in mesitylene using the procedure described above in Example 18B affords 3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine.

EXAMPLE 18BV

Heating the 1-benzyl-3-acetyl-3,4aα,5α-trimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 17 with formic acid in mesitylene using the procedure described above in Example 18B affords 3-benzyl-11(ax),6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(2-methyl-3-oxobutyl)-2,6-methano-3-benzazocine.

EXAMPLE 18BW

Heating the 1-acetyl-3-pentanoyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described above in Example 10AK with formic acid in mesitylene using the procedure described above in Example 18B affords 3-acetyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocine.

EXAMPLE 19

A. A solution of 27.0 g. (0.072 mole) of 3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18E) was dissolved in 250 ml. of 48% hydrochloric acid and the mixture heated under reflux for about eleven hours. The mixture was concentrated to a small volume in vacuo, diluted with 100 ml. of water, concentrated again, and finally boiled with about 50 ml. of isopropanol. The solid which separated was collected and dried to give 23 g. of 3-benzyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11-(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide, m.p. 156°-165° C.

Following a procedure similar to that described in Example 19A above using an appropriate 8-methoxy-3-methyl-11(ax)-R₃ -6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)--CH₂ CH₂ COR₅ -2,6-methano-3-benzazocine of formula I, the following 8-hydroxy-3-R₁ -11(ax)-R₃ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-11(eq)--CH₂ CH₂ COR₅ -2,6-methano-3-benzazocines of formula I in Table 19a were prepared where, unless noted otherwise, in each case R₂ is hydroxy, R₂ ', R₂ ", R₂ '" and R₈ are each hydrogen, and R₁, R₃ and R₄ are each methyl. The form (base or salt) of the starting material and product is given in parentheses along with the respective weights.

                  Table 19a                                                        ______________________________________                                                              Wt.S.M./    m.p.(° C.)/                            Ex.    R.sub.5       Wt.Prod.    Solv.                                         ______________________________________                                         19B    C.sub.5 H.sub.11 (b)                                                                         4.0 (salt) (a)                                                                             107-109                                                            1.8 (base)  ethanol                                       19C    C.sub.2 H.sub.5                                                                              3.5 (base)  265-268                                                            2.5 (HCl)   ethanol/ether                                 19D    C.sub.3 H.sub.7                                                                              5.0 (base)  264-266                                                            3.7 (HCl)   ethanol                                       19E    C.sub.4 H.sub.9 (b)                                                                          5.1 (base)  120-122                                                            1.9 (base)  ethyl acetate                                 19F    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                          4.0 (HCl)   260-263 (c)                                                        3.3 (HCl)   isopropanol                                   19G    C.sub.6 H.sub.13                                                                             4.5 (HCl)   206-209                                                            2.8 (HCl)   isopropanol                                   19H    C.sub.5 H.sub.11                                                                             4.5 (HCl)   252-255 (d)                                                        1.7 (HCl)   isopropanol                                   19J    CH.sub.2 CH(CH.sub.3).sub.2                                                                  5.5 (base)  251-254                                                            2.6 (HCl)   ethanol                                       19K    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2 (b)                                                      7.0 (base)  101-103.5                                                          1.6 (base)  ethyl acetate/                                                                 hexane                                        19L    (CH.sub.2).sub.2 C.sub.6 H.sub.5                                                             8.1 (salt) (a)                                                                             233-235                                                            1.6 (CH.sub.3 SO.sub.3 H)                                                                  ethanol                                       ______________________________________                                          (a) p-Toluenesulfonate                                                          (b) R.sub.3 is hydrogen                                                       (c) A sample of the racemic base was resolved with d- and 1-mandelic acid      to give, respectively, the d-mandelate, m.p. 190-193° C. (from          acetone), [α].sub.D.sup.25 = - 6.9° and the 1-mandelate, m.p      191-193° C. (from acetone), [α].sub.D.sup.25 = + 5.5°      Cleavage of the two mandelate salts to the respective free bases and           conversion of the latter to the hydrochlorides gave, respectively, the 1-      and d-hydrochlorides, m.p. 240-242° C. (from ethanol/ether),            [α].sub.D.sup.25 = - 32.2° and m.p. 240-242° C. (from      ethanol/ether), [α].sub.D.sup.25 = + 32.1°.                       (d) The methane sulfonate has m.p. 178-179° C. (from acetone).    

Following a procedure similar to that described in Example 19A above, using an appropriate 8-methoxy-3,6(eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅ -2,6-methano-3-benzazocine of formula I, the following 8-hydroxy-3,6)eq),11(ax)-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-CH₂ CH₂ COR₅ -2,6-methano-3-benzazocines are prepared where, in each case R₂ is hydroxy, R₂ ', R₂ ", R₂ '" and R₈ are each hydrogen, and R₁, R₃ and R₄ are each methyl.

                  Table 19b                                                        ______________________________________                                         Example           R.sub.5                                                      ______________________________________                                         19M               CH.sub.2 -cyclopropyl                                        19N               CH.sub.2 CH.sub.2 -cyclopropyl                               19P               CH.sub.2 -cyclobutyl                                         19Q               CH.sub.2 CH.sub.2 -cyclobutyl                                19R               CH.sub.2 -cyclopentyl                                        19S               CH.sub.2 CH.sub.2 -cyclopentyl                               19T               CH.sub.2 -cyclohexyl                                         19U               CH.sub.2 CH.sub.2 -cyclohexyl                                ______________________________________                                    

EXAMPLE 20

A. A solution of 23.1 g. (0.05 mole) of 3-benzyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-butyl)-2,6-methano-3-benzazocine hydrobromide (described in Example 19A) in 150 ml. of DMF was reduced with hydrogen over 1.0 g. of 10% palladium-on-charcoal using the procedure described above in Example 3. The product obtained was recrystallized from ethanol to give 16.1 g. of 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide, m.p. 235°-237° C. (from ethanol).

Following a procedure similar to that described in Example 20A above using an appropriate 8-R₂ -3-benzyl-11(ax)-R₃ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂ Z-2,6-methano-3-benzazocine of formula I, the following 8-R₂ -11(ax)-R₃ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I in Table 20 were prepared where in each case R₁, R₂ ', R₂ ", R₂ ''' and R₈ are hydrogen. Compounds for which no value for R₆ is given are the ketones (Z is CH₂ COR₅). Otherwise the compounds are the carbinols [Z is CH₂ C(R₅)(R₆)OH]. The form (base or salt) of the starting material and product is given in parentheses along with the respective weights.

                  Table 20                                                         ______________________________________                                                                    Wt.S.M./                                            Ex.  R.sub.2 R.sub.5 /R.sub.6                                                                       R.sub.3 R.sub.4                                                                      Wt.Prod.                                                                               m.p.(° C.)/Solv.                     ______________________________________                                         20B  CH.sub.3 O                                                                             CH.sub.3                                                                               H     21.2 (base)                                                                            189-193                                                  --      CH.sub.3                                                                             11.4 (HCl)                                                                             ethanol                                     20C  CH.sub.3 O                                                                             C.sub.5 H.sub.11                                                                       CH.sub.3                                                                             13.8 (HCl)                                                                             179-182                                                  --      CH.sub.3                                                                             5.8 (HCl)                                                                              methanol/ether                              20D  H       C.sub.5 H.sub.11                                                                       CH.sub.3                                                                             4.2 (HCl)                                                                              155-157                                                  --      CH.sub.3                                                                             2.2 (HCl)                                                                              acetone/ether                               20E  CH.sub.3 O                                                                             CH.sub.3                                                                               CH.sub.3                                                                             11.8 (HCl)                                                                             130.0-132.5                                              CH.sub.3                                                                               CH.sub.3                                                                             6.5 (base)                                                                             --                                          20F  CH.sub.3 O                                                                             C.sub.4 H.sub.9                                                                        CH.sub.3                                                                             9.0 (HCl)                                                                              170-172                                                  --      CH.sub.3                                                                             6.3 (HCl)                                                                              acetone                                     ______________________________________                                    

EXAMPLE 21

A. A mixture of 11.4 g. (0.03 mole) of 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide (described in Example 20A), 5.4 g. pg,80 of sodium bicarbonate and 5.2 g. (0.04 mole) of cyclopropylmethyl bromide in 150 ml. of DMF was heated under reflux for about nine hours and then concentrated to a small volume in vacuo. The residue was partitioned between ammonium hydroxide and ethyl acetate, the organic layer separated, and the aqueous layer extracted with additional portions of ethyl acetate. The combined extracts were washed once with water, then with brine, dried, filtered and taken to dryness to give 12.1 g. of crude product which was converted to the hydrochloride salt. The latter was recrystallized once from acetonitrile and once from ethanol/ether to give 5.2 g. of 3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 147°-154° C.

B. Following a procedure similar to that described in Example 21A, 3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (12.9 g.) was prepared by reaction of 15.0 g. (0.04 mole) of 8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 20B) with cyclopropylmethyl bromide in the presence of sodium bicarbonate in DMF.

C. 3,6(eq)-Dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine p-toluenesulfonate (9.9 g.) m.p. 199°-201° C. (from ethanol), was prepared by reductive alkylation of 11.4 g. of 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrobromide (described in Example 20A) with formaldehyde and triethylamine over palladium-on-charcoal in ethanol under about 50 p.s.i. of hydrogen using the procedure described in Example 38.

D. 3,6-(eq)-Dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (7.5 g.) was prepared by reductive alkylation of 8.2 g. of 8-methoxy-6(eq)-methyl-1,2,3,4,5,6,-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine hydrochloride (described in Example 20B) with formaldehyde and triethylamine over palladium-on-charcoal in ethanol under about 50 p.s.i. of hydrogen using the procedure described in Example 38. The hydrochloride salt gives m.p. 181°-183° C. (from ethanol).

E. 3,6-(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine hydrochloride (5.5 g.), m.p. 212°-214° C. (from acetone) was prepared by reductive alkylation of 7.2 g. of 6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine with 2.0 cc. of 37% aqueous formaldehyde and 3.8 cc. of 97% formic acid.

F. 3-Cyclobutylmethyl-6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine hydrochloride (2.1 g.), m.p. 207°-209° C. (from acetone) was prepared by reaction of 0.15 mole (from 5.9 g. of the hydrochloride) of 6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine with 2.5 g. of cyclobutylmethyl bromide in 60 ml. of DMF in the presence of 1.5 g. of sodium bicarbonate.

G. 3,6(eq),11(ax)-Trimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocine hydrochloride (3.2 g.), m.p. 209°-211° C. (from acetone/ether) was prepared by the reductive alkylation of 5.3 g. of 6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxoheptyl)-2,6-methano-3-benzazocine with 1.5 ml. of 37% aqueous formaldehyde in 100 ml. of ethanol over 1.0 g. of palladium-on-charcoal under a hydrogen pressure of about 45 p.s.i.

H. 3-Ethyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine was prepared by reaction of 0.02 mole of 6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine with 5 ml. of acetic anhydride in 50 ml. of dry pyridine. The resulting 3-acetyl-6-(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine (3.4 g., m.p. 56°-59° C.) was dissolved in 100 ml. of toluene with 11 ml. of ethylene glycol and 0.5 g. of p-toluenesulfonic acid and the mixture distilled until no further water was produced. The corresponding ethylene glycol ketal (4.0 g.) was isolated as an oil from the toluene solution after washing the latter with aqueous bicarbonate. Reduction of the ketal with 1.2 g. of lithium aluminum hydride in 150 ml. of tetrahydrofuran using the procedure described above in Example 12A afforded 1.7 g. of the final product in the form of the ethylene glycol ketal hydrochloride, m.p. 198°-201° C. (from ethyl acetate). Hydrolysis of the latter in dilute hydrochloric acid gives the free ketone.

Following a procedure similar to that described in Example 21A, using the 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described in Example 20A and an appropriate alkylating agent, R₁ Hal, there are prepared the following compounds of formula I in Table 21, where in each instance R₂ is HO; R₂ ', R₂ ", R₂ ''' and R₃ are each hydrogen; R₄ is CH₃ ; and CH₂ Z is CH₂ COCH₃.

                  Table 21                                                         ______________________________________                                         Example           R.sub.1                                                      ______________________________________                                         21J               CH.sub.2 CH═CH.sub.2                                     21K               CH.sub.2 CH═C(CH.sub.3).sub.2                            21L               CH.sub.2 C.tbd.CH                                            21M               CH.sub.2 C.tbd.CCH.sub.3                                     21N               CH.sub.2 CH═CCl.sub.2                                    ______________________________________                                    

EXAMPLE 22

A. A solution of 4.7 g. (0.16 mole) of 6(eq)-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (from the hydrochloride described in Example 18A) in 28 ml. of diethyl ether was added dropwise with stirring to 28 ml. (0.05 mole) of a 1.8M solution of methyl lithium in diethyl ether. The mixture was stirred under nitrogen for about one hour, poured into an ice/aqueous ammonium chloride solution, and the ether layer separated and washed with water. The organic layer was dried, filtered, and taken to dryness to give 4.9 g. of residue which was converted to the methanesulfonate salt in methanol/diethyl ether. The latter was recrystallized from methanol/diethyl ether to give 2.5 g. of 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 173°-174° C.

Following a procedure similar to that described in Example 22A, using an appropriate 8-R₂ -6-(eq)-R₄ -1,2,3,4,5,6-hexahydro 3-R₁ -11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described above and an appropriate lower-alkyl lithium (R₆ Li), there were prepared the 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(eq)-(3-methyl-3-hydroxy-lower-alkyl)-2,6-methano-3-benzazocines of formula I in Table 22a where, in each instance, R₂ ', R₂ ", R₂ ''' and R₇ are hydrogen. Unless noted otherwise, products were isolated as, and melting points recorded for, the free base form.

                                      Table 22a                                    __________________________________________________________________________     Example                                                                              R.sub.1 /R.sub.2                                                                       R.sub.3 /R.sub.4                                                                   R.sub.5 /R.sub.6                                                                    Wt.S.M./Wt.Prod.                                                                         m.p.(° C)/Solv.                        __________________________________________________________________________     22B   CH.sub.3                                                                               H   CH.sub.3                                                                            3.6 (base)                                                                              203-206                                              HO      C.sub.2 H.sub.5                                                                    CH.sub.3                                                                            1.2 (base)                                                                              ethyl acetate                                  22C   C.sub.3 H.sub.5CH.sub.2.sup.(a)                                                        H   CH.sub.3                                                                            4.0 (base)                                                                              184-186                                              H       C.sub.2 H.sub.5                                                                    CH.sub.3                                                                            2.2 (HCl)                                                                               CH.sub.3 CN/ether                              22D   C.sub.3 H.sub.5CH.sub.2.sup.(a)                                                        H   CH.sub.3                                                                            11.4 (base)                                                                             138-140                                              HO      CH.sub.3                                                                           CH.sub.3                                                                            3.3 (base)                                                                              ethyl acetate                                  22E   C.sub.6 H.sub.5 CH.sub.2                                                               H   CH.sub.3                                                                            3.78 (base)                                                                             252                                                  CH.sub.3 O                                                                             CH.sub.3                                                                           t-C.sub.4 H.sub.9                                                                   1.25 (HCl)                                                                              ethanol                                        22F   CH.sub.3                                                                               H   CH.sub.3                                                                            4.2 (base)                                                                              182-183                                              HO      CH.sub.3                                                                           CH.sub.3                                                                            2.6 (base)                                                                              ethyl acetate                                  22G   CH.sub.3                                                                               H   CH.sub.3                                                                            7.5 (base)                                                                              oil                                                  CH.sub.3 O                                                                             CH.sub.3                                                                           C.sub.4 H.sub.9                                                                     11.3 (base)                                             22H   C.sub.6 H.sub.5 CH.sub.2                                                               H   CH.sub.3                                                                            3.78 (base)                                                                             oil                                                  CH.sub.3 O                                                                             CH.sub.3                                                                           C.sub.2 H.sub.5                                                                     4.5 (base)                                              22J   C.sub.3 H.sub.5CH.sub.2.sup.(a)                                                        H   CH.sub.3                                                                            13.4 (base)                                                                             184-185(c)                                           HO(c)   CH.sub.3                                                                           C.sub.4 H.sub.9                                                                     10.2 (b) ethanol/ether                                  22K   C.sub.6 H.sub.5 CH.sub.2                                                               H   CH.sub.3                                                                            20.0 (base)                                                                             oil                                                  CH.sub.3 O                                                                             CH.sub.3                                                                           C.sub.3 H.sub.7                                                                     21.8(base)                                              22L   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3                                                                           CH.sub.3                                                                            11.5 (base)                                                                             223-227                                              CH.sub.3 O                                                                             CH.sub.3                                                                           t-C.sub.4 H.sub.9                                                                   2.4 (HCl)                                                                               ethanol/ether                                  22M   C.sub.3 H.sub.5 CH.sub.2.sup.(a)                                                       H   CH.sub.3                                                                            12.0 (base)                                                                             --                                                   CH.sub.3 O                                                                             C.sub.2 H.sub.5                                                                    t-C.sub.4 H.sub.9                                                                   12.9 (base)                                                                             --                                             22N   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3                                                                           CH.sub.3                                                                            18.8 (HCl)                                                                              246-248                                              H       CH.sub.3                                                                           t-C.sub.4 H.sub.9                                                                   3.6 (HCl)                                                                               ethanol/ether                                  22P   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3                                                                           CH.sub.3                                                                            13.7 (base)                                                                             233-234                                              CH.sub.3 O                                                                             CH.sub.3                                                                           CH.sub.3                                                                            12.1 (HCl)                                                                              ethanol/ether                                  22Q   C.sub.6 H.sub.5 CH.sub.2                                                               H   t-C.sub.4 H.sub.9                                                                   37.7 (base)                                                                             249                                                  CH.sub.3 O                                                                             CH.sub.3                                                                           CH.sub.3                                                                            8.7 (HCl)                                                                               ethanol/ether                                  22R   C.sub.6 H.sub.5 CH.sub.2                                                               CH.sub.3                                                                           t-C.sub.4 H.sub.9                                                                   11.9 (base)                                                                             249-252                                              CH.sub.3 O                                                                             CH.sub.3                                                                           CH.sub.3                                                                            4.0 (HCl)                                                                               ethanol                                        __________________________________________________________________________      .sup.(a) Cyclopropylmethyl                                                     .sup.(b) Methanesulfonate                                                      .sup.(c) Starting material was methyl ether described in Example 21B, and      the product obtained from reaction with butyl lithium was cleaved, withou      characterization, to the 8-HO compound with sodium propanethiol using the      procedure described in Example 26A.                                      

Following a procedure similar to that described in Example 22A, using an appropriate 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ CH₂ COR₅ -2,6-methano-3-benzazocine described above and an appropriate lower-alkyl, phenyl or phenyl-lower-alkyl lithium, R₆ Li, there are obtained the respective 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ CH₂ C(R₅)(R₆)OH-2,6-methano-3-benzazocines of formula I listed in Table 22b where, in each instance, R₂ ', R₂ ", R₂ ''', R₇ and R₈ are hydrogen.

                                      Table 22b                                    __________________________________________________________________________     Example                                                                              R.sub.1      R.sub.2  R.sub.3                                                                            R.sub.4                                                                            R.sub.5                                                                            R.sub.6                                __________________________________________________________________________     22S   C.sub.6 H.sub.11                                                                            CH.sub.3 S                                                                              H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22T   4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       CH.sub.3 O                                                                              H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22U   4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                       CH.sub.3 CONH                                                                           H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22V   4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        C.sub.2 H.sub.5 OCONH                                                                   H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22W   4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                           H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22X   3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                             H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22Y   3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                    H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22Z   4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                               H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22AA  3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22AB  3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                            H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22AC                                                                                  ##STR41##   H        H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                               22AD  CH.sub.3     H        H   C.sub.2 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    CH.sub.3                               22AE  CH.sub.3     H        H   C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           C.sub.6 H.sub.5                        22AF  CH.sub.3     H        CH.sub.3                                                                           C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           C.sub.6 H.sub.5 CH.sub.2 CH.sub.2      __________________________________________________________________________

EXAMPLE 22AG

Reaction of 3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18BJ) with methyl lithium in diethyl ether using the procedure described in Example 22A affords 3,6(eq),9-trimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylbutyl)-2,6-methano-3-benzazocine.

EXAMPLE 23

A. Reaction of the 3-[2-(4-fluorophenyl)ethyl]-8-ethoxycarbonylamino-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in Example 22V) with aqueous alkali in ethanol affords 3-[2-(4-fluorophenyl)ethyl]-8-amino-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine.

Following a procedure similar to that described in Example 23A, the following 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(eq)-(3-methyl-3-hydroxy-lower-alkyl)-2,6-methano-3-benzazocines of formula I are also prepared:

B. 3-[2-(3-Hydroxyphenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine by alkaline hydrolysis of 3-[2-(3-acetoxyphenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in Example 22X); and

C. 3-[2-(3-Aminophenyl)ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine by alkaline hydrolysis of 3-[2-(3-acetylaminophenyl)-ethyl]-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in Example 22AB).

EXAMPLE 24

A. Reaction of 8-hydroxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine (described in Example 22F) with acetic anhydride affords 8-acetoxy-3,6(eq)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-acetoxybutyl)-2,6-methano-3-benzazocine.

Following a procedure similar to that described in Example 24A, using the 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-hydroxybutyl)-2,6-methano-3-benzazocine described in Example 22A and an appropriate acid chloride in the presence of pyridine, there are obtained the following 3-methyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-3-R.sub.7 O-butyl)-2,6-methano-3-benzazocines of formula I in Table 24 where, in each instance, R₁, R₅ and R₆ are CH₃ ; R₂, R₂ ', R₂ ", R₂ ''', R₃ and R₈ are each hydrogen; and R₄ is C₂ H₅.

                  Table 24                                                         ______________________________________                                         Example         R.sub.7                                                        ______________________________________                                         24B             C.sub.6 H.sub.5 CO                                             24C             4-CH.sub.3 C.sub.6 H.sub.4 CO                                  24D             3-CH.sub.3 OC.sub.6 H.sub.4 CO                                 24E             4-ClC.sub.6 H.sub.4 CO                                         24F             4-BrC.sub.6 H.sub.4 CO                                         24G             4-FC.sub.6 H.sub.4 CO                                          24H             3-CF.sub.3 C.sub.6 H.sub.4 CO                                  ______________________________________                                    

EXAMPLE 25

A. The 3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxooctyl)-2,6-methano-3-benzazocine p-toluenesulfonate (15.9 g., 0.03 mole) described in Example 18H was hydrolyzed to the free base, and the latter (10.5 g.) dissolved in diethyl ether was added to a stirred slurry of 600 mg. (0.005 mole) of lithium aluminum hydride in ether. The mixture was refluxed for one hour, quenched by the careful addition of 1.2 ml. of water in 10 ml. of tetrahydrofuran followed by excess dilute sodium hydroxide, filtered and the filtrate evaporated to dryness. The residue (10 g.) was converted to the p-toluenesulfonate salt which was recrystallized from ethanol/ether to give 6.2 g. of 3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxyoctyl)-2,6-methano-3-benzazocine p-toluenesulfonate, m.p. 135°-137° C.

B. Reaction of 3-cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (described in Example 18D) with lithium aluminum hydride in diethyl ether using the procedure described in Example 25A affords 3-cyclopropylmethyl-6(eq)-ethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3hydroxybutyl)-2,6-methano-3-benzazocine.

EXAMPLE 26

A. A solution of 4.72 g. (0.01 mole) of 3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine (described in Example 22E) in 50 ml. of DMF was reduced with hydrogen over 0.5 g. of palladium-on-charcoal under a hydrogen pressure of about 50 p.s.i. using the procedure described in Example 3. When reduction was complete, the catalyst was removed by filtration, and the solution, containing 6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine was treated with 1.68 g. (0.02 mole) of sodium bicarbonate and 2.0 g. (0.015 mole) of cyclopropylmethyl bromide, and the mixture was warmed with stirring on a steam bath for one hour.

The reaction mixture containing crude 3-cyclopropylmethyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine, was distilled at atmospheric pressure, collecting 25 ml. of distillate, and then treated with 2.1 g. (0.05 mole) of a 57% dispersion of sodium hydride in mineral oil and 5 ml. of DMF. The mixture was cooled in an ice bath and treated dropwise with stirring under nitrogen with 4.6 ml. of propanethiol. After refluxing and stirring for about four hours, the reaction mixture was poured into a solution of aqueous ammonium chloride and extracted with 50 ml. of diethyl ether. The product was isolated in the usual manner in the form of the free base which was recrystallized from ethanol to give 2.4 g. of 3-cyclopropylmethyl-6(eq)-methyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine, m.p. 195°-198° C. The methanesulfonate gave m.p. 232° C.

Following a procedure similar to that described in Example 26A, using an appropriate 8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-3-benzyl-11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocine and an appropriate alkylating agent, R₁ -Hal, (or reductive alkylation with formaldehyde and formic acid using the procedure described in Example 38), there were obtained the 8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I in Table 26 where, in each instance unless noted otherwise, R₂ is hydroxy; R₂ ', R₂ ", R₂ ''', R₇ and R₈ are each hydrogen; and R₄ is CH₃. Compounds for which no value for R₆ is given are the ketones (Z is CH₂ COR₅). The compounds are otherwise the carbinols [Z is CH₂ C(R₅)(R₆)OH]. Melting points of the products are given in each case for the methanesulfonate salt, and yields are also given for the methanesulfonate unless noted otherwise.

                  Table 26                                                         ______________________________________                                         Ex.  R.sub.1 /R.sub.3                                                                          R.sub.5 /R.sub.6                                                                       Wt.S.M./Wt. Prod                                                                          m.p. (° C.)/Solv.                    ______________________________________                                         26B  CH.sub.3   CH.sub.3                                                                               4.72 (HCl) 206-208                                          H          t-C.sub.4 H.sub.9                                                                      2.7        methanol/ether                              26C  CH.sub.3   CH.sub.3                                                                               10.9 (base)                                                                               144-146                                          H          C.sub.3 H.sub.7                                                                        7.4 (base) acetone                                     26D  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             CH.sub.3                                                                               2.5 (HCl)  249-252                                          CH.sub.3   t-C.sub.4 H.sub.9                                                                      1.4        methanol/ether                              26E  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             CH.sub.3                                                                               9.2 (base) 182-183                                          H          C.sub.3 H.sub.7                                                                        1.8        ethanol/ether                               26F  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             CH.sub.3                                                                               12.9 (base)                                                                               225-228                                          H(b)       t-C.sub.4 H.sub.9                                                                      0.42       methanol/ether                              26G  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             t-C.sub.4 H.sub.9                                                                      3.4 (HCl)  266-268                                          CH.sub.3   CH.sub.3.sup.c                                                                         1.4        methanol/ether                              26H  CH.sub.3   t-C.sub.4 H.sub.9                                                                      4.9 (HCl)  219-223 (base)                                   CH.sub.3   CH.sub.3                                                                               1.1 (base) ethyl acetate                               26J  CH.sub.3   CH.sub.3                                                                               11.8 (HCl) 179-182 (base)                                   CH.sub.3   CH.sub.3                                                                               1.3 (base) ethyl acetate                               26K  CH.sub.3   C.sub.4 H.sub.9                                                                        9.0 (HCl)  283-285 (HCl)                                    CH.sub.3   --      2.1 (HCl)  methanol/ether                              26L  CH.sub.3   t-C.sub.4 H.sub.9                                                                      4.7 (HCl)  190-195.sup.d                                    CH.sub.3   --      1.5 (d)    ethanol/ether                               26M  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             t-C.sub.4 H.sub.9                                                                      12.3 (HCl) 248-250                                          H          CH.sub.3.sup.d                                                                         1.3        methanol/ether                              26N  C.sub.3 H.sub.5CH.sub.2.sup.a                                                             CH.sub.3                                                                               11.8 (HCl) 236-238 (HCl)                                    CH.sub.3   CH.sub.3                                                                               1.2 (HCl)  ethanol                                     26P  C.sub.4 H.sub.7CH.sub.2.sup.e f                                                           C.sub.5 H.sub.11                                                                       5.9 (HCl)  213-216 (HCl)                                    CH.sub.3   --      3.2 (HCl)  isopropanol                                 26Q  CH.sub.3   t-C.sub.4 H.sub.9                                                                      2.4 (HCl)  242-247.sup.g                                    CH.sub.3   CH.sub.3                                                                               2.4 (CH.sub.3 SO.sub.3 H)                                                                 methanol                                    26R  CH.sub.3   t-C.sub.4 H.sub.9                                                                      5.2 (HCl)  212-215                                          H          CH.sub.3                                                                               2.3 (CH.sub.3 SO.sub.3 H)                                                                 methanol                                    ______________________________________                                          .sup.a Cyclopropylmethyl                                                       .sup.b R.sub.4 is C.sub.2 H.sub.5                                              .sup.c Isomeric with compound of Example 26D which was prepared via            compound of Example 22L. Compound of Example 26G prepared via compound of      Example 18L.                                                                   .sup.d Ethanesulfonate. Isomeric with compound of Example 26A which was        prepared via compound of Example 18E. Compound of Example 26M prepared vi      compound of Example 18K.                                                       .sup.e Cyclobutylmethyl                                                        .sup.f Debenzylated product reacted with 0.013 mole of cyclobutane             carboxylic acid chloride in chloroform in the presence of triethylamine,       and the resulting amide, without purification, converted to the ethylene       glycol ketal by reaction with ethylene glycol in the presence of               p-toluenesulfonic acid in toluene. The ketal was then reduced in               tetrahydrofuran with lithium aluminum hydride using the procedure of           Example 12A and the product, identical with the compound of Example 21F,       isolated from an acid medium and then cleaved with sodium propylsulfide.       .sup.g Isomeric with the compound of Example 26H. Isomers both prepared b      reaction of ethyl lithium with the same t-butyl ketone (R.sub.5 is             t-C.sub.4 H.sub.9). Isomeric products, i.e.                                    3-benzyl-6(eq),11(ax)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-     ydroxy-3,4,4-trimethyl-pentyl)-2,6-methano-3-benzazocine, are readily           separated from one another in the crude product by conversion to the           hydrochloride salt. One isomeric form is insoluble in ethanol and gives        rise to the isomer of Example 26H. The other, much more soluble in             ethanol, gives rise to the isomer of Example 26Q. The isomer of Example        26Q predominates over that of Example 26H when methyl lithium is reacted       with the t-butyl ketone. The opposite is true when t-butyl lithium is          reacted with the methyl ketone (R.sub.5 is CH.sub.3).                    

EXAMPLE 27

Using a procedure similar to that described above in Example 26A, 3.19 g. (0.007 mole) of 3-benzyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine (described in Example 22N) was debenzylated by reduction over 0.35 g. of palladium-on-charcoal and the resulting 6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine reacted with 2.0 g. (0.015 mole) of cyclopropylmethyl bromide and 1.7 g. (0.020 mole) of sodium bicarbonate and the product isolated in the form of the hydrochloride salt to give 1.5 g. of 3-cyclopropylmethyl-6(eq),11(ax)-dimethyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3,4,4-trimethylpentyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 232°-233° C. (from ethanol/ether).

EXAMPLE 28

A. A solution of 15 g. (0.04 mole) of 3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxo-butyl)-2,6-methano-3-benzazocine (described in Example 18E) was catalytically debenzylated and the resulting nor-base alkylated with cyclopropylmethyl bromide in the presence of sodium bicarbonate using the procedure described in Example 26A. The resulting 3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine (12.9 g.) was dissolved in 125 ml. of toluene and added to 45 ml. of a 2.1M solution of n-butyl lithium in hexane at -65° C. using the procedure described in Example 22A. The resulting 3-cyclopropylmethyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine (13.4 g.) was dissolved in 130 ml. of DMF and the ether group cleaved by treatment with 7.1 g. (0.168 mole) of a 57% mineral oil dispersion of sodium hydride and 12.8 g. (0.168 mole) of propanethiol in the manner described above in Example 26A. The product was converted to the methanesulfonate salt which was recrystallized from ethanol/ether to give 10.2 g. of 3-cyclopropylmethyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 184°-185° C.

Following a procedure similar to that described in Example 28A, using the 3-benzyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-oxobutyl)-2,6-methano-3-benzazocine described in Example 18E, ethyl lithium and an appropriate alkylating agent, R₁ -Hal, (or reductive alkylation with formaldehyde and formic acid using the procedure described in Example 38), there were obtained the 8-hydroxy-3-R₁ -6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylpentyl)-2,6-methano-3-benzazocines of formula I in Table 28 where, in each instance, R₂ is hydroxy; R₂ ', R₂ ", R₂ '", R₃, R₇ and R₈ are hydrogen; R₄ and R₅ are CH₃ ; and R₆ is C₂ H₅. In each instance, the melting points are given for the methanesulfonate salt, and the yield of product is given for the free base.

                  Table 28                                                         ______________________________________                                         Ex.   R.sub.1      Wt.S.M./Wt.Prod.                                                                            m.p. (° C.)/Solv.                       ______________________________________                                         28B   cyclopropyl-CH.sub.2                                                                         15.0 (base)  195-196                                                           8.3 (base)   acetone                                       28C   CH.sub.3      15.0 (base)  155-157                                                           11.0 (base)  ethanol                                       ______________________________________                                    

EXAMPLE 29

A 5.7 g. sample of 3-methyl-8-methoxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine described in Example 22G in DMF was cleaved with sodium propylsulfide (0.063 mole) using the procedure described in Example 26A and the product (3.4 g. of crude base) converted to the methanesulfonate salt which was recrystallized from ethanol/ether to give 2.6 g. of 3-methyl-8-hydroxy-6(eq)-methyl-1,2,3,4,5,6-hexahydro-11(eq)-(3-hydroxy-3-methylheptyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 184°-186° C.

Following a procedure similar to that described in Example 29A using an appropriate 8-methoxy-6(eq)-methyl-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-3-R₁ -11(eq)-CH₂ Z-2,6-methano-3-benzazocine, the following 8-hydroxy-6(eq)-methyl-11(ax)-R₃ -1,2,3,4,5,6-hexahydro-3-R₁ -11(eq)-CH₂ Z-2,6-methano-3-benzazocines of formula I were prepared where, in each case R₂ ', R₂ ", R₂ ''', R₇ and R₈ are hydrogen; R₄ is CH₃ ; and R₂ is hydroxy. Where no value for R₆ is given, the compound has the ketone structure (Z is CH₂ COR₅) but otherwise has the carbinol structure [Z is CH₂ C(R₅) (R₆)OH].

                  Table 29                                                         ______________________________________                                         Ex.  R.sub.1 /R.sub.3                                                                          R.sub.5 /R.sub.6                                                                       Wt.S.M./Wt.Prod.                                                                          m.p. (° C.)/Solv.                    ______________________________________                                         29B  CH.sub.3   C.sub.5 H.sub.11                                                                       6.4 (base) 176-177.sup.a                                    H          H       1.8.sup.a  acetone                                     29C  C.sub.3 H.sub.5CH.sub.2                                                                   C.sub.4 H.sub.9                                                                        5.0 (base) 235-237 (HCl)                                    CH.sub.3   --      2.5 (HCl)  isopropanol                                 ______________________________________                                          .sup.a p-Toluenesulfonate                                                

EXAMPLE 30

A. A solution of 1.8 g. (0.0046 mole) of 1-benzyl-3-(2-hydroxy-2-propyl)-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline hydrochloride (described in Example 11D) was dissolved in 100 ml. of mesitylene and the solution treated with 3.8 ml. (0.1 mole) of formic acid and refluxed and stirred for about 24 hours. On cooling, the mixture was extracted with three 5 ml. portions of 1M phosphoric acid, and the combined aqueous extracts washed twice with diethyl ether and then basified by the cautious addition of 6.6 g. of potassium hydroxide pellets. The oil which separated was extracted with diethyl ether, and the ether extracts worked up in the usual manner to give an oil which was converted to the hydrochloride salt. The latter was recrystallized from ethanol/ether to give 0.3 g. of 3-benzyl-6(eq)-methyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine hydrochloride, m.p. 232°-235° C.

B. Following a procedure similar to that described in Example 30A, 19.6 g. (0.062 mole) of 1-methyl-3-(2-hydroxy-2-propyl)-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 9F in 1 liter of mesitylene and 38 ml. of formic acid was heated and stirred under reflux for 24 hours and worked up in the manner described in Example 30A to give 8.5 g. (0.028 mole) of 3,6(eq)-dimethyl-8-methoxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine as an oil which, without further characterization, was cleaved with 0.15 mole of sodium propylsulfide in 75 ml. of DMF using the procedure described in Example 26A. The product was converted to the methanesulfonate salt which was recrystallized from ethanol to give 1.6 g. of 3,6(eq)-dimethyl-8-hydroxy-1,2,3,4,5,6-hexahydro-11(eq)-(3-methyl-2-butenyl)-2,6-methano-3-benzazocine methanesulfonate, m.p. 226°-229° C.

Following a procedure similar to that described in Example 30A, using the 7-R₂ -1-R₁ -3-C(R₅) (R₆)OR₇ -4aα-R₃ -5α-R₄ -1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinolines described in Examples 9A, 9B, 9C, 9D, 9G, 9E, 11A, 11C and 13A in refluxing mesitylene/formic acid, there are obtained the respective 8-R₂ -6(eq)-R₄ -1,2,3,4,5,6-hexahydro-3-R₁ -11(ax)-R₃ -11(eq)-(2-lower-alkenyl)-2,6-methano-3-benzazocines of formula I in Table 30 where, in each instance, R₂ ', R₂ ", R₂ ''' and R₈ are hydrogen.

                  Table 30                                                         ______________________________________                                         Example                                                                               R.sub.1      R.sub.2                                                                               R.sub.3                                                                             R.sub.4                                                                              R.sub.5                                                                             R.sub.6                             ______________________________________                                         30C    CH.sub.3     H      H    C.sub.3 H.sub.7                                                                      CH.sub.3                                                                            CH.sub.3                            30D    CH.sub.3     H      H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            CH.sub.3                            30E    CH.sub.3     H      H    CH.sub.3                                                                             CH.sub.3                                                                            CH.sub.3                            30F    CH.sub.3     HO     H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            CH.sub.3                            30G    cyclopropyl-CH.sub.2                                                                        H      H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            CH.sub.3                            30H    C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                           H      H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            CH.sub.3                            30J    CH.sub.3     H      H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            C.sub.3 H.sub.7                     30K    CH.sub.3     H      CH.sub.3                                                                            C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            CH.sub.3                            30L    CH.sub.3     H      H    C.sub.2 H.sub.5                                                                      CH.sub.3                                                                            H                                   ______________________________________                                    

EXAMPLE 31

A. Two grams of the solid hydrochloride salt obtained as an initial precipitate from the ethanol/ether crystallization in Example 18A was recrystallized once again from ethanol/ether to give 1.3 g. of 1,2-dimethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline hydrochloride, m.p. 262°-264° C.

A solution of 5.3 g. (0.017 mole) of the latter in 50 ml. of ethanol was reduced with 0.1 g. of platinum oxide. When reaction was complete, the catalyst was removed by filtration, and the product isolated in the form of the hydrochloride salt in the usual manner to give 2.4 g. of 1,2-dimethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline hydrochloride, m.p. 319°-329° C.

The following 1-R₁ -2-methyl-4aα-R₃ -5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formula IIIa in Table 31a where, in each instance, R₂, R₂ ', R₂ " and R₂ ''' are hydrogen; R₄ is C₂ H₅ and Q is CH₃ were obtained as by-products with the main products of Examples 18C and 18D, respectively. The yields and melting points for the compounds of Examples 31B and 31C are given for the hydrochloride and p-toluenesulfonate salts, respectively.

                  Table 31a                                                        ______________________________________                                         Ex.  R.sub.1     R.sub.3                                                                               Wt.II/Wt.IIIa                                                                             m.p. (° C.)/Solv.                    ______________________________________                                         31B  CH.sub.3    CH.sub.3                                                                              10 (base)  234-235                                                             1.2        acetone                                     31C  cyclopropyl-CH.sub.2                                                                       H      16 (base)  187-189                                                             2.5        ethyl acetate                               ______________________________________                                    

The following 1-R₁ -2-Q-4aα-R₃ -5α-R₄ -7-R₂ -8-R₂ '-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines of formula IIIa, where R₂ " and R₂ ''' in each instance are hydrogen, are obtained as by-products from the preparations described, respectively, in Examples 18E, 18K, 18P, 18Q, 18R, 18S, 18T, 18U, 18V, 18W, 18X, 18Y, 18Z, 18AA, 18AB, 18AC, 18AD, 18AE, 18AF, 18AG, 18AH, 18AJ, 18AK, 18AL, 18AM, 18AN, 18AQ, 18AR, 18AS, 18AT, 18AU and 10D.

                                      Table 31b                                    __________________________________________________________________________     Example                                                                              R.sub.1 /Q    R.sub.2 /R.sub.2 '                                                                      R.sub.3 /R.sub.4                                  __________________________________________________________________________     31D   C.sub.6 H.sub.5 CH.sub.2                                                                     CH.sub.3 O                                                                              H                                                       CH.sub.3      H        CH.sub.3                                          31E   C.sub.6 H.sub.5 CH.sub.2                                                                     H        H                                                       CH.sub.3      H        C.sub.2 H.sub.5                                   31F   CH.sub.3      H        H                                                       C.sub.3 H.sub.7                                                                              H        C.sub.2 H.sub.5                                   31G   C.sub.6 H.sub.11                                                                             CH.sub.3 S                                                                              H                                                       CH.sub.3      H        CH.sub.3                                          31H   4-BrC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        CH.sub.3 O                                                                              H                                                       CH.sub.3      H        CH.sub.3                                          31J   4-ClC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                        CH.sub.3 CONH                                                                           H                                                       CH.sub.3      H        CH.sub.3                                          31K   4-FC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                         C.sub.2 H.sub.5 OCONH                                                                   H                                                       CH.sub.3      H        CH.sub.3                                          31L   4-Cl-3-CH.sub.3 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                            H        H                                                       CH.sub.3      H        CH.sub.3                                          31M   3-CH.sub.3 COOC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                              H        H                                                       CH.sub.3      H        CH.sub.3                                          31N   3,4-(CH.sub.3 O).sub.2 C.sub.6 H.sub.3 CH.sub.2 CH.sub.2                                     H        H                                                       CH.sub.3      H        CH.sub.3                                          31P   4-CH.sub.3 SC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                H        H                                                       CH.sub.3      H        CH.sub.3                                          31Q   3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                                 H        H                                                       CH.sub.3      H        CH.sub.3                                          31R   3-CH.sub.3 CONHC.sub.6 H.sub.4 CH.sub.2 CH.sub.2                                             H        H                                                       CH.sub.3      H        CH.sub.3                                          31S                                                                                   ##STR42##    H        H                                                       CH.sub.3      H        CH.sub.3                                          31T   CH.sub.3      H        H                                                       CH.sub.3      Cl       CH.sub.3                                          31U   CH.sub.3      H        H                                                       CH.sub.3      Br       CH.sub.3                                          31V   CH.sub.3      H        H                                                       CH.sub.3      F        CH.sub.3                                          31W   CH.sub.3      H        H                                                       CH.sub.3      CF.sub.3 CH.sub.3                                          31X   CH.sub.3      H        H                                                       CH.sub.3      CH.sub.3 CH.sub.3                                          31Y   CH.sub.3      C.sub.6 H.sub.5                                                                         H                                                       CH.sub.3      H        CH.sub.3                                          31Z   CH.sub.3 CH.sub.3                                                                             ##STR43##                                                                              H CH.sub.3                                        31AA  CH.sub.3      H        H                                                       CH.sub.3      H        H                                                 31AB  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub. 2 CH.sub.2 Cl                             31AC  CH.sub.3 CH.sub.3                                                                            H H                                                                                      ##STR44##                                        31AD  CH.sub.3 CH.sub.3                                                                            H H                                                                                      ##STR45##                                        31AE  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub.2 CH.sub.2 OCH.sub.3                       31AF  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub.2 CH.sub.2 SC.sub.6 H.sub.5                31AG  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub.2 CH.sub.2 SOC.sub.6 H.sub.5               31AH  CH.sub.3      H        H                                                       CH.sub.3      H        CHCH.sub.2                                        31AJ  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub.2 CH.sub.2 SCH.sub.3                       31AK  CH.sub.3      H        H                                                       CH.sub.3      H        CH.sub.2 CH.sub.2 OH                              31AL  CH.sub.3      H        H                                                       C.sub.6 H.sub.5                                                                              H        C.sub.2 H.sub.5                                   __________________________________________________________________________

EXAMPLE 31AM

Heating the 1,5α,8-trimethyl-3-acetyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline described in Example 2AR with formic acid in mesitylene using the procedure described in Example 18B affords, in addition to the benzazocine of formula I described in Example 18AU, 1,2,5α,8-tetramethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]-quinoline.

Reduction of the compounds disclosed in Examples 31D-31AM, inclusive, with hydrogen over platinum oxide using the procedure described in Example 31A affords the corresponding 1-R₁ -2-Q-4aα-R₃ -5α-R₄ -7-R₂ -8-R₂ '-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinolines of formula IIIb.

EXAMPLE 32

A. Hydrolysis with aqueous alkali in an ethanol solvent of 1-[2-(4-chlorophenyl)ethyl]-7-acetylamino-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline and 1-[2-(4-chlorophenyl)ethyl]-7-acetylamino-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline (described in Example 31J) afford, respectively, 7-amino-1-[2-(4-chlorophenyl)-ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline and 7-amino-1-[2-(4-chlorophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]-quinoline.

Following a procedure similar to that described in Example 32A, the following compounds of formulas IIIa and IIIb are similarly prepared:

B. 7-Amino-1-[2-(4-fluorophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline and 7-amino-1-[2-(4-fluorophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a, 5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline, by alkaline saponification, respectively, of 1-[2-(4-fluorophenyl)ethyl]-2,5α-dimethyl-7-ethoxycarbonylamino-1,2,3,4,4a,5,10,10a-octahydro-3,5-etheneobenzo[g]quinoline and 1-[2-(4-fluorophenyl)-ethyl]-2,5α-dimethyl-7-ethoxycarbonylamino-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline (described in Example 31K);

C. 1-[2-(3-Aminophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline and 1-[2-(3-aminophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline, by alkaline saponification, respectively, of 1-[2-(3-acetylaminophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline and 1-[2-(3-acetylaminophenyl)ethyl]-2,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline (described in Example 31R).

EXAMPLE 33

A solution of 88 g. (0.33 mole) of 2-(4-methoxybenzyl)-8-methylene-3-azabicyclo[3.3.1]non-6-en-4-one (described in Example 15A) was dissolved in a solution of 800 ml. of glacial acetic acid and 180 ml. of concentrated sulfuric acid, and the mixture stirred and heated on a steam bath for one hour. The mixture was then poured into four liters of an ice/water mixture. The gum which separated slowly solidified and was collected and recrystallized three times from DMF to give 4.3 g. of 7-methoxy-5α-methyl-3,4,4a,5,10,10a-hexahydro-3,5-ethenobenzo[g]quinoline-2-(1H)-one, m.p. 268°-272° C.

EXAMPLE 34

A solution of 5.38 g. (0.02 mole) of 7-methoxy-5α-methyl-3,4,4a,5,10,10a-hexahydro-3,5-ethenobenzo[g]quinoline-2-(1H)-one (described in Example 33) in 250 ml. of tetrahydrofuran was added slowly to a stirred suspension of 1.52 g. (0.04 mole) of lithium aluminum hydride in 108 ml. of tetrahydrofuran, and the mixture was heated under reflux for one and one half hours and then worked up in the manner described above in Example 12A. The product was isolated in the form of the hydrochloride salt which was recrystallized from ethanol/diethyl ether to give 3.08 g. of 7-methoxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline hydrochloride, m.p. 254°-255° C.

EXAMPLE 35

A solution of 18.0 g. (0.07 mole) of 7-methoxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline hydrochloride (described in Example 34) in 200 ml. of ethanol was reduced with hydrogen over 1.8 g. of palladium-on-charcoal under a hydrogen pressure of about 55 p.s.i. When reduction was complete, the product was worked up in the manner described above in Example 3 to give 3.6 g. of 7-methoxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline, m.p. 82°-84° C. (from hexane).

EXAMPLE 36

A. A solution of 12.0 g. (0.047 mole) of 7-methoxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]-quinoline hydrochloride (described in Example 34) in 60 ml. of 48% hydrobromic acid was refluxed and stirred for 15 minutes, then cooled and worked up in the manner described above in Example 19A. The product was isolated in the form of the free base to give 5.7 g. of 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline, m.p. 298°-310° C. (from DMF);

B. Following a procedure similar to that described in Example 36A, 12.5 g. (0.049 mole) of 7-methoxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline (described in Example 35) was reacted with 62 ml. of 48% hydrobromic acid, and the product, in the form of the hydrobromide salt, was recrystallized from water to give 5.6 g. of 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline hydrobromide, m.p. 305°-311° C.

EXAMPLE 37

A mixture of 4.8 g. (0.02 mole) of 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]-quinoline (described in Example 36A), 1.7 g. (0.02 mole) of sodium bicarbonate and 1.9 ml. (0.022 mole) of allyl bromide in 50 ml. of DMF was heated with stirring under reflux for one hour and then worked up in the manner described above in Example 7A. The product was isolated in the form of the hydrochloride salt which was recrystallized from ethanol/diethyl ether to give 2.6 g. of 1-allyl-7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,4-ethenobenzo[g]quinoline hydrochloride, m.p. 246°-248° C.

Following a procedure similar to that described in Example 37A, using the 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline or the 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]-quinoline described in Examples 36A and 36B, respectively, and an appropriate alkylating agent, R₁ -Hal, there are prepared the corresponding 1-R₁ -7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinolines and 1-R₁ -7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinolines of formulas IIIa and IIIb, respectively, in Table 37 below where, in each instance, R₂ ', R₂ ", R₂ ''' and R₃ are hydrogen; Q is H₂ ; R₂ is HO; and R₄ is CH₃. The yields of products and the melting points are given, in each case, for the hydrochloride salts unless noted otherwise. The nature of the starting material and final product, whether the 3,5-etheno compounds of formula IIIa or the 3,5-ethano compounds of formula IIIb, is indicated by the designations IIIa and IIIb, respectively.

                                      Table 37                                     __________________________________________________________________________     Example R.sub.1 Wt.S.M.                                                                               Wt.Prod.                                                                             m.p. (° C.)                                                                    Solvent                                    __________________________________________________________________________     37B                                                                               (IIIa)                                                                              C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      4.82 (base)                                                                           5.4   190-192                                                                               ethanol/                                                                       ether                                      37C                                                                               (IIIb)                                                                              CH.sub.2CHCH.sub.2                                                                     6.5 (HBr)                                                                             5.3   238-241                                                                               ethanol/                                                                       ether                                      37D                                                                               (IIIb)                                                                              C.sub.6 H.sub.5 CH.sub.2 CH.sub.2                                                      6.49 (HBr)                                                                            5.1   259-262 ethanol                                   37E                                                                               (IIIa)                                                                              C.sub.3 H.sub.7                                                                        4.82 (base)                                                                           3.8.sup.a                                                                            210-211.sup.a                                                                         CH.sub.3 CN/                                                                   ether                                      37F                                                                               (IIIb)                                                                              C.sub.3 H.sub.5CH.sub.2.sup.b                                                          6.49 (HBr)                                                                            2.5   252    ethanol/                                                                       ether                                      37G                                                                               (IIIb)                                                                              C.sub.3 H.sub.7                                                                        6.49 (HBr)                                                                            3.1   260-264                                                                               ethanol/                                                                       ether                                      37H                                                                               (IIIa)                                                                              C.sub.3 H.sub.5CH.sub.2.sup.b                                                          4.82 (base)                                                                           2.6   251-253.sup.c                                                                         ethanol/                                                                       ether                                      __________________________________________________________________________      .sup.a Methanesulfonate salt                                                   .sup.b Cyclopropylmethyl                                                        .sup.c Hydrobromide                                                     

EXAMPLE 38

A mixture of 4.82 g. (0.02 mole) of 7-hydroxy-5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]-quinoline (described in Example 36A), 1.6 ml. (0.02 mole) of 37% aqueous formaldehyde and 100 ml. of ethanol was reduced with hydrogen over 2 g. of palladium-on-charcoal using a Parr-shaking apparatus. When reduction was complete, the mixture was worked up in the manner described above in Example 3 and the product isolated in the form of the hydrochloride salt to give 3.6 g. of 1,5α-dimethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethenobenzo[g]quinoline hydrochloride, m.p. 302°-305° C. (from ethanol/diethyl ether);

B. Following a procedure similar to that described in Example 38A, a mixture of 6.49 g. (0.02 mole) of 7-hydroxy 5α-methyl-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]-quinoline hydrobromide (described in Example 36B), 1.6 ml. (0.02 mole) of 37% aqueous formaldehyde and 2.8 ml. (0.02 mole) of triethylamine in 100 ml. of ethanol was reduced with hydrogen over 2 g. of palladium-on-charcoal and the product isolated in the form of the hydrochloride salt to give 2.8 g. of 1,5α-dimethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-3,5-ethanobenzo[g]quinoline hydrochloride, m.p. 318° C. (from water).

BIOLOGICAL TEST RESULTS

The compounds of formula I are generally active in the acetylcholine-induced abdominal constriction test (Ach), a primary analgesic screening test, and also in the rat tail flick radiant thermal heat analgesic test (Tail Flick Agon.) A few species have also been tested and found active in the phenyl-p-quinone-induced writhing (PPQ) and the anti-bradykinin (BK) tests, which are also primary analgesic screening procedures. Data so obtained for the compounds, identified by reference to the preceding examples and expressed either in terms of the ED₅₀ (mg./kg., subcutaneous administration) or in terms or percent inhibition, are given below. All doses are expressed in milligrams per kilogram (mg./kg.).

    ______________________________________                                                                            Tail Flick                                  Example                                                                               Ach      PPQ      BK        Agonist                                     ______________________________________                                         18A    1.7      --       --        14±2                                     18B    0.3      --       --        6.9±0.8                                  18C    1.1      --       --        11±1.0                                   18D    7.4      64%/50   --        Inact.                                      18H    18       --       40%/10    Inact./240                                  18M    1.9      --       --        5.9±0.95                                 18N    0.89     --       --        2.0±0.22                                 18P    87%/75   --       --        Inact.                                             33%/25                                                                  18S    1.0      --       --        4.3±0.52                                 18V    2.0      --       2.4       16±3.3                                   19B    1.4      --       0.24      42±21                                    19C    ˜0.18                                                                             --       --        0.99±0.14                                19D    0.023    --       --        0.099±0.014                              19E    0.19     --       --        0.95±0.11                                19F    0.074             0.032     47%/240                                     19G    12       --       2.2       Inact.                                      19H    0.24     0.28     0.043     Inact.                                             26(p.o.) 7.8(p.o.)                                                      20C    13       --       0%/50     40%/60(i.p.)                                                         100%/50(i.p.)                                         20D    2.7      --       --        25%/30                                      21A    8.9      --       --        Inact.                                      21C    6.9      --       --        64±12                                    21E    1.5      --       --        30±7.4                                   21F    13%/75   --       --        Inact.                                             77%/75                                                                  21H    7%/75    --       --        Inact.                                             13%/25                                                                  22A    1.6      --       --        11±2.2                                   22B    2.1      --       --        10%/60                                      22C    4.7      11       --        Inact.                                      22D    16       --       --        --                                          22F    8.2      5.9      --        --                                          25A    2.8      --       --        60±6.9                                   26A    <25, <75 --       --        --                                          26B    40%/75   --       --        Inact.                                      26C    2.6      --       --        68±14                                    26D    67%/75;  --       --        Inact.                                             33%/25                                                                  26E    7.6      --       --        Inact.                                      26F    34       --       --        Inact./60                                   26G    8.9      --       Inact.    Inact.                                      26H    100%/75  --       --        Inact.                                             47%/25                                                                  26J    3.8      --       7.9       Inact.                                      26K    0.017    --       0.012     0.039±0.006                              26L    6.6      --       ˜5  Inact.                                      26M    9.0      --       --        Inact.                                      26N    4.5      --       --        Inact.                                      26P    20%/75   --       --        Inact./120(i.p.)                                   27%/25                                                                  27     33%/75;  --       --        Inact./120                                         13%/25                                                                  28A    6.5      --       --        Inact.                                      28B    7.9      --       --        Inact.                                      28C    3.3      --       --        43%/240                                     29A    2.5      --       --        ˜60                                   29B    1.4      --       0.70      --                                          29C    93%/75   --       --        Inact.                                             13%/25                                                                  ______________________________________                                    

The compounds of Examples 18D, 19P, 19F, 19G, 19H, 21A, 22D, 26A, 26G, 26J, 26L, 26M, 26N, 28A, 29C and 26P have also been found to be active in the phenazocine tail flick antagonist test, the ED₅₀ (subcutaneous administration) for those species being, respectively, 24, 7.8, ˜0.58, 0.040, 0.008 (0.098 vs. morphine), 0.088, 0.046, 0.27, 0.71, 2.3, 2.4, 1.1, 0.006, 0.025, 0.0034 and 0.26 mg./kg.

The compounds of formulas IIIa and IIIb are generally active in the same primary analgesic screening tests, the acetylcholine-induced abdominal constriction and the phenyl-p-quinone-induced writhing tests. Data so-obtained are given below, all doses being expressed in mg./kg.

    ______________________________________                                         Example/Formula                                                                               Ach        PPQ                                                  ______________________________________                                         31A/IIIa       2.7        --                                                   31A/IIIb       17         --                                                   31B/IIIa       1.6        20                                                   31C/IIIa       4.1        36                                                   33/IIIa        Inact.     --                                                   34/IIIa        4.6        17                                                   35/IIIb        5.1        13                                                   36A/IIIa       3.5        Inact.                                               37A/IIIa       11         --                                                   37B/IIIa       1.4        10                                                   37C/IIIb       12         Inact.                                               37D/IIIb       16         Inact.                                               37E/IIIa       4.5        --                                                   37F/IIIb       3.2        100%/70                                                                        43%/35                                               37G/IIIb       13         43                                                   38A/IIIa       1.9        23                                                   38B/IIIb       3.0        23                                                   ______________________________________                                    

Finally, certain species of formula II have been found active in the acetylcholine-induced abdominal constriction test and the anti-bradykinin test, both of which are primary analgesic screening tests, thus indicating usefulness of these species as analgesics, in addition to their usefulness as intermediates for the preparation of the products of formulas I and IIIa. The data so-obtained on subcutaneous administration expressed either in terms of the ED₅₀ 's or the percent inhibition for the acetylcholine constriction test or in terms of the percent protection of the pain response elicited by intraarterial bradykinin injection (the anti-bradykinin test) are given below.

    ______________________________________                                         Example    Ach           BK                                                    ______________________________________                                         5B         33%/75        --                                                               13%/25                                                              5C         8.6           20%/10                                                                         20%/100                                               5D         87%/75        --                                                               27%/25                                                              6D         18            Act.                                                  6L         22            55                                                               73%/150(p.o.)                                                                  33%/50(p.o.)                                                        6M         19            --                                                    6N         100%/75       --                                                               13%/25                                                              9H         4.4           40%/10                                                                         20%/100(Inact.)                                       2AD        20%/75                                                                         33%/25                                                              7R         0%/75         --                                                               13%/25                                                              ______________________________________                                    

In addition the compound of Example 5C was found to have an ED₅₀ (s.c.) of 36 mg./kg. in the phenyl-p-quinone-induced writhing test. 

I claim:
 1. A compound having the formula ##STR46## where R₁ is hydrogen, lower-alkyl, lower-alkanoyl (only when R₄ is hydrogen), lower-alkenyl, lower-alkynyl, halo-lower-alkenyl, cycloalkyl, cycloalkyl-lower-alkyl, phenyl-lower-alkyl, phenyl-lower-alkyl substituted in the phenyl ring by a single trifluoromethyl or by from one to two members of the group consisting of halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, amino, lower-alkanoyl-amino or a single methylenedioxy attached to adjacent carbon atoms, or R₁ is 2- or 3-furylmethyl or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups; R₂, R₂ ', R₂ " and R₂ '" are each hydrogen, or three of them are hydrogen and the fourth is halogen, lower-alkyl, hydroxy, lower-alkanoyloxy, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, nitro, amino, lower-alkanoylamino, lower-alkoxycarbonylamino or phenyl, or two of the adjacent such groups together are methylenedioxy; R₃ is hydrogen or lower-alkyl; R₄ is hydrogen, lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkylthio-lower-alkyl, lower-alkylsulfinyl-lower-alkyl, phenylthio-lower-alkyl, phenylsulfinyl-lower-alkyl, lower-alkenyl or halo-lower-alkyl, or R₃ and R₄ together are divalent lower-alkylene, --(CH₂)_(n) --, where n is one of the integers 3 or 4; R₈ is hydrogen or lower-alkyl; and Y is carboxy, cyano, carbo-lower-alkoxy, COR₅, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl, or a group of the formula: ##STR47## where R₅ and R₆ are the same or different members selected from the group consisting of hydrogen, lower-alkyl, cycloalkyl-lower-alkyl, phenyl or phenyl-lower-alkyl; and R₇ is hydrogen, lower-alkanoyl, benzoyl, or benzoyl substituted by a single trifluoromethyl or by one to three sterically compatible members of the group consisting of lower-alkyl, lower-alkoxy, hydroxy or halo, and wherein cycloalkyl, all occurrences, is a group having from 3 to 7 carbon atoms or is alkyl-substituted cycloalkyl having a total of from 3 to 8 carbon atoms, 3 to 7 of which are cycloalkyl ring carbon atoms, or an acid-addition salt thereof.
 2. A compound having the formula: ##STR48## where R₁ is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl-lower-alkyl or 2- or 3-furylmethyl, or such 2- or 3-furylmethyl substituted on the unsubstituted ring carbon atoms by from one to three methyl groups; R₂, R₂ ', R₂ " and R₂ '" are each hydrogen, or three of them are hydrogen and the fourth is hydroxy or lower-alkoxy; R₃ is hydrogen or lower-alkyl; R₄ is lower-alkyl, lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, phenylthio-lower-alkyl or lower-alkenyl; Y is carboxy, carbo-lower-alkoxy, COR₅, COO-lower-alkylene-cycloalkyl, COO-lower-alkylene-phenyl, or a group of the formula ##STR49## where R₅ and R₆ are the same or different members selected from the group consisting of hydrogen, lower-alkyl, phenyl or phenyl-lower-alkyl; R₈ is hydrogen or lower-alkyl; and R₇ is hydrogen, lower-alkanoyl, benzoyl or benzoyl substituted by a single trifluoromethyl or by from one to three sterically compatible members of the group consisting of lower-alkyl, lower-alkoxy, hydroxy or halo, and wherein cycloalkyl, all occurrences, is a group having from 3 to 7 carbon atoms or is alkyl-substituted cycloalkyl having a total of from 3 to 8 carbon atoms, 3 to 7 of which are cycloalkyl ring carbon atoms, or an acid-addition salt thereof.
 3. A compound according to claim 2 where Y is carboxy.
 4. A compound according to claim 2 where Y is carbo-lower-alkoxy.
 5. A compound according to claim 2 where Y is lower-alkanoyl.
 6. A compound according to claim 2 where Y is the group ##STR50##
 7. 1-Methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid according to claim
 3. 8. 1-Benzyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid according to claim
 3. 9. 1-Methyl-5α-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid according to claim
 3. 10. 1,5α-Dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid according to claim
 3. 11. 5α-Ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylic acid according to claim
 3. 12. Ethyl 1-benzyl-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 13. Methyl 1,5α-dimethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline -3-carboxylate according to claim
 4. 14. Ethyl 1-methyl-5α-propyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 15. Ethyl 1-methyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 16. Methyl 1,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 17. Ethyl 5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 18. Ethyl 1-cyclopropylmethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 19. Ethyl 4aα,5α-dimethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline-3-carboxylate according to claim
 4. 20. 1-Benzyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahyro-2,5-methanobenzo[g]quinoline according to claim
 5. 21. 1,4aα-Dimethyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 22. 1-Benzyl-3-acetyl-5α-methyl-7-methoxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 23. 1-Benzyl-3-acetyl-5α-methyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 24. 3-Acetyl-5α-methyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 25. 1-Cyclopropylmethyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 26. 1-Methyl-3-acetyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 27. 1-Methyl-3-butyryl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 28. 1-Methyl-3-acetyl-5α-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 5. 29. 1-Methyl-3-(2-hydroxy-2-propyl)-5α-propyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 30. 1Methyl-3-(2-hydroxy-2-propyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 31. 1,5α-Dimethyl-3-(2-hydroxy-2-propyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 32. 1-Methyl-3-(2-hydroxy-2-propyl)-5α-ethyl-7-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline accroding to claim
 6. 33. 1-Cyclopropylmethyl-3-(2-hydroxy-2-propyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 34. 1-(2-Phenylethyl)-3-(2-hydroxy-2-propyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 35. 1-Methyl-3-(2-hydroxy-2-pentyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 36. 1,4aα-Dimethyl-3-(2-hydroxy-2-propyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 37. 1-Methyl-3-hydroxymethyl-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 38. 1-Methyl-3-(1-hydroxyethyl)-5α-ethyl-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 39. 4aα,5α-Dimethyl-3-(2-hydroxy-2-propyl)-1,2,3,4,4a,5,10,10a-octahydro-2,5-methanobenzo[g]quinoline according to claim
 6. 